Structure-Activity Relationships of the Benzimidazole Opioids: Nitazenes and Piperidinylbenzimidazolones (Cychlorphine, Brorphine, Bezitramide Derivs) - [Vol 1: Nitazenes]

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By: Oxycosmopolitan X.com/DuchessVonD
Patreon.com/Oxycosmopolitan
u/jtjdp
AskChemistry
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The world of chemistry pulsates with the creative energy of its practitioners. It is a realm where imagination takes flight, conjuring new molecules with the potential to revolutionize how we treat disease, understand life, or even alter the course of human history. However, the journey from conception to tangible reality is fraught with difficulty. Unexpected hurdles lie in wait. Transforming a dream molecule into a practical therapeutic is far from guaranteed. Failure awaits most ventures. These failures are studied, formulas improved. Failure breeds success. Success is founded in failure.
“If you aren’t frustrated, you aren’t doing hard science.” Repeatedly beating one’s head against the wall is a hallmark of great scientists. Those with unmarred foreheads, like my own, are usually just mediocre. I’m too vain to be anything but mediocre.
The modern chemist operates within a complex landscape. Gone are the days of unfettered exploration, where ideas could blossom unhindered. Instead, regulations and obligations hold sway, demanding careful consideration and responsible practice. Yet, amidst these constraints, a multitude of approaches exist to guide the design of these coveted molecules.
One particularly reliable approach involves drawing inspiration from the success of existing structures. By studying molecules with established efficacy, the chemist embarks on a quest to improve upon their therapeutic potential through targeted molecular modifications. This journey of optimization, fueled by both creative vision and scientific rigor, lies at the heart of this fascinating field.
Fifteen years ago, at the beginning of my chemical career, an era when I spent more time hitting on boys than I did the books, I was inspired by the resonant beauty of a different type of beau. It was neither furbaby, frat boy, or the cute nerd from the library: it was benzimidazole – my bundle of aromatic joy!
More specifically, I was attracted to the NOP/ORL1 and μ-opioidergic potential [http://dx.doi.org/10.1021/bk-2013-1131.ch008] of the relatively niche 2-benzimidazolone derivatives that were first pioneered by Paul Janssen in the early 1960s. The marriage of 2-benzimidazolone resonance with the C4 position of piperidine gave birth to a scaffold with diverse pharmacology: the 4-(2-keto-1-benzimidazolyl)piperidines. Also referred to as piperidinylbenzimidazolones or the more “Charmed” nomenclature, 4-benzimidazolonepiperidines.
The 4-(2-oxo-benzimidazolyl)piperidine scaffold was first utilized by Janssen to grow his portfolio of antipsychotic-neuroleptic agents. Janssen coupled the piperidinylbenzimidazolone moiety with a halogenated N-butyrophenone to form the dopamine antagonists benperidol, droperidol and domperidone. Concurrent with the discovery of neuroleptics of the benzimidazolone series were opioidergic members based on the same scaffold. There is significant overlap in Janssen’s diverse portfolio of dopamine antagonists with those of his opioid portfolio. Most of Janssen’s classical neuroleptic scaffolds are readily converted to highly selective μ-opioid receptor agonists by replacing the butyrophenone moiety with an opioactive moiety. The most active of these include:
p-Halogenated benzyl (brorphine; clorphine)
N-cyanoethyl + p-halo benzyl (cychlorphine, cybrorphine): analgesic activity up to 230 x morphine
p-Methyl benzyl (warorphan): 130 x morphine
Methadyl (R4847; etodesitramide): up to 200 x morphine
Diphenylbutyronitrile (bezitramide, desitramide): 10-15 x morphine
Diphenylpropyl (R5460): 60 x morphine
Additional opioid-activating moieties are found in the following diagram (not a comprehensive list).
[https://i.imgur.com/Lb3lHYE.jpg]
[REFS: Janssen - Drugs Affecting the Central Nervous System, Vol 2 (1968) - A Burger, ed.; https://doi.org/10.1016/0014-2999(83)90331-x; https://doi.org/10.1016/0014-2999(77)90025-5; https://doi.org/10.1208/aapsj070234; https://doi.org/10.1016/s0960-894x(03)00665-6; https://doi.org/10.1248/cpb.49.1314]
Janssen’s 2-benzimidazolone odyssey culminated in the clinical development of the long-acting analgesic bezitramide (100 x pethidine). Despite its potential, bezitramide was poorly soluble with low bioavailability and did not see widespread adoption. He would continue to utilize the scaffold in his psychiatric portfolio, but bezitramide was the last commercial venture in its class.
Other members of the class, especially those derived from N-despropionyl bezitramide, are highly active opioid analgesics with potencies ranging from 10-230 x morphine. Research into the scaffold was revived by Kennedy et al. as a platform for developing biased μ-opioid receptor (μOR) agonists. [https://doi.org/10.1021/acs.jmedchem.8b01136] Several of the ligands from the 2018 study have appeared as designer drugs, including brorphine and the 5,6-dichloro congener SR-17018.
The piperidinylbenzimidazolone series was initially developed alongside fentanyl – the most successful of Janssen’s opioid discoveries. The 2-benzimidazolones can be imagined as closed-ring analogs of the propionanilide substructure within the fentanyl molecule (see red arrow in the diagram below).
The evolution of the piperidinylbenzimidazolones from their humble methadylic and fentanylic roots and their latter-day ethylenediamine derivatives is outlined in the following diagram:
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https://preview.redd.it/ptocngnmz8nc1.jpg?width=2402&format=pjpg&auto=webp&s=fdc327a99ef9c5a74a1aab830a293197e0eb24fd
[https://i.imgur.com/4Qy3RRl.jpg]
Members of the piperidinylbenzimidazolones, such as cychlorphine and its congeners, will be more fully explored in the second volume of this two-part series.
The first volume is dedicated to members of the nitazene series: 2-benzylbenzimidazoles.
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Karma is a Benzimidazole, who doesn't play with balls (Deandra’s Version)
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Benzimidazole stands out as a prominent player in the realm of heterocyclic pharmacophores, earning the reputation as a privileged structure due to its frequent presence in bioactive molecules [https://doi.org/10.1016%2Fj.jscs.2016.08.001]. This unique aromatic scaffold emerges from the fusion of two aromatic rings: benzene and imidazole. As an amphoteric moiety, benzimidazole embodies characteristics of both acids and bases. Additionally, benzimidazoles have the ability to form salts, further broadening their potential.
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https://preview.redd.it/x3mldahxz8nc1.jpg?width=955&format=pjpg&auto=webp&s=6edae983dd7da7d0ca86b503866d355e27a9b839
[https://i.imgur.com/coC3yjd.jpg]
This unique structure imbues its derivatives with interesting properties and diverse chemical reactivity. [https://doi.org/10.1016%2Fj.apsb.2022.09.010]
The benzimidazole structure offers a unique combination of aromatic character and planarity, contributing significantly to its properties and reactivity. [https://doi.org/10.3390%2Fmolecules28145490] Both the benzene and imidazole rings exhibit aromaticity, granting them stability due to delocalization of π-electrons throughout the conjugated system. [https://doi.org/10.1039/B40509] This aromaticity also translates to a planar structure for the molecule, enabling crucial interactions with biological targets. This planarity facilitates π-π stacking, where the π-electron clouds of the benzimidazole ring overlap favorably with aromatic moieties present in the active sites of target receptors. These interactions, driven by transient electrostatic forces, contribute to the stabilization of the complex and enhance the binding affinity of the benzimidazole moiety to its target. [https://doi.org/10.1107%2FS1600536809027391]
While the aromatic framework confers stability, the presence of nitrogen atoms in the imidazole ring introduces a degree of polarity. This polarity arises from the uneven distribution of electrons, rendering the molecule slightly basic. These nitrogen atoms also contribute to the amphoteric nature of benzimidazole. Depending on the reaction environment, the molecule can act as an acid by donating a proton (H+) from the NH group, or as a base by accepting a proton from an acidic species.
The unique electronic distribution within the benzimidazole structure influences the reactivity profile of this versatile substrate. [http://dx.doi.org/10.2174/1570179420666221010091157] The positions 4, 5, 6, and 7 (relative to the imidazole ring) are electron-rich. This electron-rich character makes these positions susceptible to attack by electrophilic reagents, leading to reactions like nitration, halogenation, and sulfonation. Conversely, the 2-position exhibits electron deficiency due to the electron-withdrawing nature of the adjacent aromatic ring. This electron deficiency makes the 2-position a favorable target for nucleophiles, facilitating nucleophilic substitution reactions. This specific reactivity is particularly relevant in the context of 2-benzylbenzimidazoles, where the 2-position serves as the anchor point for the para-substituted benzyl moiety present in compounds like etonitazene. Benzimidazole generally displays resistance towards both oxidation and reduction reactions. However, under harsh conditions, the benzene ring can be susceptible to oxidation. Conversely, the aromatic character of the molecule contributes to its resistance towards reduction. The acid/base properties of benzimidazoles are due to the stabilization of the charged ion by the resonance effect.
The substitution pattern of benzimidazole derivs (such as nitazenes) influences the reactivity of different regions of the molecule and alters its physicochemical properties. [https://doi.org/10.2174/1389557519666191122125453]
The two nitrogens of benzimidazole have different properties and acidities, increasing the ring system’s electronic diversity and utility as a synthetic scaffold. The pyridine-like nitrogen, aza (–N=), is an electron donor (labeled N1 in diagram), while the pyrrole-like nitrogen, an amine (–NH–), acts as an electron acceptor (labeled N2).
Benzimidzole’s nitrogens are somewhat less basic than the corresponding pair in plain vanilla imidazole. This makes benzimidazoles more soluble in polar solvents and less soluble in organics. Unsubstituted benzimidazole, for example, is soluble in hot water but poorly soluble in ether and insoluble in benzene.
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https://preview.redd.it/gcil3y0zz8nc1.jpg?width=878&format=pjpg&auto=webp&s=16f814d564613672a9e31534a74f991c11b8dffc
[https://i.imgur.com/9DjyBfU.jpg]
In unsubstituted benzimidazole, a rapid proton exchange occurs between the nitrogen atoms (–NH– and =N– see above figure). This phenomenon, known as tautomerism, gives rise to two equivalent forms of the molecule that exist in an equilibrium. The transformation can occur either between individual benzimidazole molecules or with the help of protic solvents like water. This exchange makes substituents at the C5 and C6 positions chemically identical. However, the magic fades once you introduce a substituent to the N1 nitrogen (N-substituted benzimidazoles). This disrupts the dance, locking the molecule into two distinct and isolatable forms, like twins that can finally be told apart. [https://doi.org/10.1016/0169-4758(90)90226-t90226-t)]
As the nitazene species are highly substituted benzimidazoles, the position of the substituent along the C5-C6 benzene axis is just as critical to bioactivity as the nature of the substituent itself. The opioidergic activity of the C5-C6 regioisomers of the nitro nitazenes varies substantially. In the case of the series prototype etonitazene (5-nitro), shifting the nitro group from C5 to C6 results in an activity loss of nearly 100-fold. [https://doi.org/10.1039/J39660001511]
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[ABOVE: Anatomy of 2-benzylbenzimidazole prototype, etonitazene, featuring optimal substituents: 5-nitro (electron withdrawing group = EWG), 2-benzyl (p-ethoxy optimal), ethylenediamine side chain (diethylamino optimal)]
[https://i.imgur.com/dF1ZnXz.jpeg]
As with chemical reactivity, the solubility of substituted benzimidazoles varies. The aliphatic side chain (blue in diagram) and 2-benzyl substituent (green) of etonitazene contribute to a very high lipid solubility. The ionization constant of the diethylaminoethyl side chain (branching from the pyrrole nitrogen) contributes to greater acidic character compared to the unsubstituted benzimidazole. Combined with the increased lipophilicity, this translates to lower aqueous solubility and increased solubility in organic solvents. The ionization constants (pKa) for the nitrogens in etonitazene are as follows: pyrrole-type (N2) is 2.86 and that of the aminoethyl side-chain (N3) is 6.36. [https://doi.org/10.1111/j.2042-7158.1966.tb07782.x]
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https://preview.redd.it/9ky1ghx309nc1.jpg?width=3551&format=pjpg&auto=webp&s=5cb67cf4a5a1a5bb6a0a0bb928c8a8eca9d3eb66
[https://i.imgur.com/39pQFP9.jpeg]
[ABOVE: The anatomy of piperidinylbenzimidazolone opioid analgesics. The 2-benzimidazolone core of series prototype (brorphine) attaches to C4 of the piperidine ring, forming the crucial 4-piperidinylbenzimidazolone core]
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History
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The path to fully synthetic opioids began with the elucidation of the chemical structure of morphine. [Mem. Proc. Manchester Lit. Philos. Soc. 1925, 69(10), 79] Before the vast array of analytical tools we take for granted today, pinpointing the exact structure of complex natural products like morphine was a major challenge. Gulland-Robinson (1925) and Schopf (1927) independently proposed the structure we now accept, but only the 1952 total synthesis of morphine by Gates and Tschudi [https://doi.org/10.1021/ja01124a538] confirmed it definitively. Just two years later, Elad and Ginsburg reported an intermediate convertible to morphine, solidifying the picture
With a rudimentary framework of morphine’s structure, researchers sought an improved drug with better oral activity and less addiction potential. In 1929, a US National Research Council program embarked on this mission, systematically modifying the morphine molecule and establishing the structure-activity relationships (SAR) of the 4,5-epoxymorphinan class. This small group included Nathan B. Eddy and EL May, who would later become leaders in the field of addiction research. The aim of their 11-year odyssey was to discover improved analgesics through elucidation of simpler fragments of the morphine molecule. While contributing greatly to the structure-activity relationships of morphine derivatives, their ultimate goal of discovering less addictive narcotics was elusive. Two morphine analogs resulting from the project, desomorphine and metopon, demonstrated reduced dependence potential. Based on the recent emergence of Krokodil (homebake desomorphine) on the Russian exotic reptile market, it seems doubtful that the reduced addiction liability of desomorphine observed in rodents translates to humans. [NB Eddy, “The National Research Council Involvement in the Opiate Problem, 1928-1971” (1973)]
Before the spindly 11-year odyssey of their American colleagues concluded, a series of discoveries at German pharma firm Hoechst AG would rock the field of analgesics like a blitzkrieg bukkake. Eisleb introduced the first fully synthetic opioid when he synthesized pethidine (meperidine) in 1937 [https://doi.org/10.1055/s-0028-1120563], followed by Schaumann’s elucidation of its morphine-like mechanism of action a year later. Later that same year (1938), Hoechst’s chief of R&D, Max Bockmuhl, and his eventual successor, Gustav Ehrhart, discovered morphine-like analgesia in a series of straight-chain diphenylpropylamine derivatives [https://doi.org/10.1002/jlac.19495610107]. The prototypes of this class, methadone and its α-methyl isomer isomethadone, would go on to inspire many of the first synthetic opioids introduced to the clinic (dipipanone, phenadoxone, dextromoramide, normethadone, LAAM, dextropropoxyphene). Aspects of this 3,3-diphenylpropylamine scaffold, such as the ethylamino side chain and the methadyl moiety, would be incorporated into the design of 2-benzylbenzimidazole and 2-benzimidazolone opioids.
To learn more about the chemistry and pharmacology of methadone, isomethadone and other 3,3-diphenylpropylamine opioids, see my review here: [https://www.reddit.com/usejtjdp/comments/11jbjmy]
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Percocet in Peacetime
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The immediate postwar period ushered in an explosion of research dedicated to the elusive "Holy Grail" of analgesics: a pain reliever devoid of the dark side. These ideal analgesics would have fewer side effects, such as respiratory depression, constipation, sedation and dependence liability. In this “morphine python quest for the holy grail,” several key discoveries stand out.
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https://preview.redd.it/hya6t67b09nc1.jpg?width=5981&format=pjpg&auto=webp&s=6e8261d7228e5914df9ead6e0f0524fbe1baf40a
[https://i.imgur.com/0hHsSz6.jpeg]
The structural complexity of morphine presents a significant challenge to the natural product chemist. The cis-(1,3-diaxial) geometry of the iminoethano bridge (the top half of the piperidine; ring D) frustrated early attempts at total synthesis of this molecule and its relatives. Much of the early work, in fact, focused on construction of a “model hydrophenanthrene” scaffold containing the important quaternary center (corresponding to C13 in the morphinan skeleton). A cyclodehydration reaction developed in the course of this research provided a necessary tool for much of the subsequent work.
The speculative scheme for the biological origins of morphine, as proposed by Robinson and Schopf in the mid-late 1920s, is likely to have inspired the successful synthetic scheme for prep’n of simpler versions of the morphine nucleus. These proposals detailed the cyclization of a benzylisoquinoline into the desired morphinan nucleus. Another 40 years would pass before these postulates were confirmed by studies involving the (in vivo) conversion of radiolabeled norlaudanosoline into morphine (in plant tissue).
Using the postulates of Robinson-Schopf as templates, the young chemist Rudolph Grewe prepared a substituted 1-benzyloctahydroisoquinoline (known in industry as “octabase”). Grewe spent the better part of a decade (1942-49) tinkering with different cyclization conditions in order to convert octabase into the cis-(1,3-diaxial)-fused morphinan structure observed in morphine. This ring closure was accomplished via a carbonium ion mechanism and effected by heating octabase in concentrated phosphoric acid, yielding the morphinan nucleus – see (14R)-levorphanol in the above figure. Levorphanol was a useful addition to the clinicians toolkit. It was the first analgesic to pair supra-morphine potency with substantially reductions in dependence liability. Levorphanol has been used for decades as a tolerance-attenuation agent in high-dose morphine patients (attributed to levorphanol’s `incomplete cross-tolerance’ with other opioid analgesics).
For a detailed review of Grewe Cyclization, see my reddit post: [https://www.reddit.com/AskChemistry/comments/p4z5sx/]
While the holy grail of opioid analgesics devoid of side-effects remained elusive, the outlook among opioid researchers was one of optimism.
The year 1952 saw the formal synthesis of morphine by Gates & Tschudi [https://doi.org/10.1021/ja01124a538]. Their achievement holds a distinguished position in the annals of organic chemistry, not just for being the first, but also for its impact on the field of natural product chemistry. This synthesis marked a pivotal moment in the field of total synthesis by showcasing the potential of the Diels-Alder reaction for the construction of complex structures. [https://doi.org/10.1021/ja01630a108] This powerful reaction, forming a cyclic structure from two simpler molecules, became a cornerstone in organic synthesis, employed in numerous subsequent syntheses of natural products and pharmaceuticals. A decade after Gates’ total synthesis, KW Bentley utilized [4+2] cycloaddition [https://doi.org/10.1016/j.ejmech.2020.112145] to systematically explore a series of Diels-Alder adducts of thebaine, i.e. 6,14-endoethenooripavines (“orvinols”). His discoveries in this class were so numerous, that they have been given their own class: the aptly named “Bentley Compounds.” [doi.org/10.1111/j.2042-7158.1964.tb07475.x] Bentley’s research resulted in several currently marketed drugs, including buprenorphine and dihydroetorphine (used primarily for opioid maintenance), and etorphine/diprenorphine (used in veterinary medicine). [https://doi.org/10.1016/B978-0-08-010659-5.50011-1] The Bentley series is noteworthy for high analgesic potency and their ability to substitute for opioid dependency with minimal side effects. Dihydroetorphine, upwards of 10,000 fold more potent than morphine, is used extensively in China as a maintenance medication and has an exemplary safety record. [https://doi.org/10.1111%2Fj.1527-3458.2002.tb00236.x]
Total synthesis provided researchers access to the synthetic dextro-antipodes of morphine and the inactive enantiomers of related 4,5-epoxymorphinans. [https://doi.org/10.1039/JR9540003052] Access to the unnatural (+)-morphine enantiomer helped researchers elucidate the complex stereochemistry of the 4,5-epoxymorphinan nucleus, which remains the most popular class of opioids in modern pharmacopeia. [https://doi.org/10.1021/acschemneuro.0c00262]
For a review of the history and chemistry of the morphinan superfamily, see my reddit post: [https://www.reddit.com/AskChemistry/comments/opnszl]
In 1954, AH Beckett and AF Casy published one of the most influential theories of the early opioid era: the Beckett-Casy Postulate [https://doi.org/10.1111/j.2042-7158.1954.tb11033.x]. The researchers analyzed the structure-activity relationships of morphine-like agents and proposed a set of structural, steric, and electronic requirements that were shared among the opioid ligands of the era. This became a proto “opioid pharmacophore,” that is, a rough template of the structural requirements for high activity at the proposed “Morphine Receptor.” The existence of a common site of action among morphine-like agents was supported by what was known at the time: stereotypical “narcotic cues” demonstrated by animals upon administration of both semi-synthetic and fully synthetic analgesics (Straub tail, anti-mydriasis, respiratory depression, antidiarrheal, cough suppression). While the quantitative potency varies widely (i.e. fentanyl vs codeine), the qualitative effects of analgesia and the side-effects following drug administration are consistent across natural and synthetic morphine-like agents. This formed the basis of the theory of a common site of action.
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1954 Beckett-Casy Postulate - early Model of the mu Opioid Receptor
[https://i.imgur.com/epFABkr.jpg]
While the proposed pharmacophore held a more humble understanding than modern receptor theories, the Beckett-Casy Postulate (also known as the “Morphine Rule”) was impressive given that the “analog models” of the era were still crafted by hand and often molded out of papier mache. The hypothesis provided a convenient rule of thumb used by drug designers to quickly determine the likelihood of a compound having morphine-like activity. Compounds conforming to the rule were explored further, while structures that didn’t obey were made to sleep in the doghouse until they learned proper manners. Their theory combined the earlier SARs of morphine derivatives elucidated by NB Eddy during the 1930s with those of the newfangled fully synthetic analgesics, such as methadone and pethidine.
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Core features essential for strong opioidergic activity (Beckett-Casy Postulate)
[https://i.imgur.com/hEjeDlg.jpg]
The following core structural features were determined to be essential for strong analgesic activity:

1. An aromatic ring system: provides a platform for π-π stacking interactions with amino acid residues at the μ-receptor active site.
2. The aromatic ring is attached to a quaternary carbon.
3. Ethylene bridge. The quaternary carbon is linked to a basic amine via an ethylene bridge, that is, a two carbon chain. This flexible linker allows for the conformational freedom necessary for optimal receptor binding.
4. Basic amine separated from the quaternary center by a two carbon spacer. The amine forms a critical salt bridge with the Asp149 residue in the human μ-receptor (Asp147 in the murine sequence). The amine requirement remains true for virtually every class of opioid. Exceptions to the rule emerged in the early 2000s when Prisinzano et al. discovered non-nitrogenous Salvinorin A analogs with high μOR affinity (i.e. herkinorin).

Beckett & Casy developed their theory by comparing the shared structural features of morphine analogs with those of early synthetic opioids, including levorphanol, pethidine and methadone.
The figure below shows the structural features common to morphine (pentacyclic 4,5-epoxymorphinan) and prototypes from three important synthetic opioid classes: levorphanol (tetracyclic morphinan), pethidine (4-phenylpiperidine) and methadone (3,3-diphenylpropylamine).
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https://preview.redd.it/i54h2chp09nc1.jpg?width=3487&format=pjpg&auto=webp&s=9f0d22653daa1b44da5319307d22d973569d6d2b
[https://i.imgur.com/hE0eAp4.jpeg]
While the morphine rule offers a valuable framework for understanding opioid activity, there are exceptions and limitations. One of the first challenges to the universality of the Morphine Rule came from a key structural feature of the nitazenes: the diamine side chain.
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Enter Nitazene…
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In 1957, researchers at CIBA (Hoffmann, Hunger, Kebrle, Rossi) found that a minimally substituted 2-benzylbenzimidazole, 1-(β-diethylaminoethyl)-2-benzylbenzimidazole, induced a Straub tail response in mice. The Straub tail reaction is a highly sensitive narcotic cue that is indicative of morphine-like mechanism of action. Despite lacking the potency-enhancing accouterments of etonitazene (5-nitro and p-ethoxybenzyl substituents), this homely-looking structure demonstrated analgesic activity on par with codeine (one-tenth morphine). This finding was of sufficient interest to spur elucidation of the structure-activity relationships of this novel series. And so the ugly duckling benzimidazole became the proteus of a dynasty.
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https://preview.redd.it/7734j43s09nc1.jpg?width=2116&format=pjpg&auto=webp&s=8972f550794ffeb2662aa14d9347f20d2ff81a49
[https://i.imgur.com/RoTsrOO.jpg]
At the time of the discovery of the nitazenes, the diamine system was an uncommon structure within the opioids.
Most clinical opioids are monoamines. One nitrogen to rule them all. In the morphinan class, nitrogen functionalization outside of the 17-amine position (the iminoethane bridge) is rare. The addition of multiple nitrogens into the morphinan nucleus has a deleterious effect on activity.
At the same time as the discovery of the 2-benzylbenzimidazoles, researchers at American Cyanamid discovered a series of morphine-like diamine analgesics based on the N-(tert-aminoalkyl)-propionanilide scaffold, including phenampromide and diampromide (Pat # US2944081A; https://doi.org/10.1021/jo01061a049]. As with nitazenes, the design of the ampromide class was influenced by lessons learned from the 3,3-diphenylpropylamine series [https://doi.org/10.1002/jps.2600511131].
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https://preview.redd.it/nwemwk5u09nc1.jpg?width=4375&format=pjpg&auto=webp&s=48c1e75b753a7a7d5956be815d9456a51a032200
[https://i.imgur.com/WEhPd6w.jpg]
The nitazenes were the first opioid analgesics to successfully incorporate the diamine into a highly active μ opioid pharmacophore. This dynamic amine system contributes to the high activity observed in the series. It consists of two basic moieties: the pyrrole-like nitrogen incorporated into the aromatic benzimidazole system and a tertiary amine in the side chain. This diamine function endows them with the ability to exhibit both acidic and basic character depending on the surrounding environment. This is known as amphoterism.
The benzimidazole ring system experiences a reduction in apparent basicity due to the electron-withdrawing nitro group substitution. In etonitazene, the benzimidazole amine has a pKa of 2.86. This translates to an estimated 22% of the molecule being protonated at physiological pH (7.4). Conversely, the side chain amine boasts a higher pKa of approximately 6.36.
Furthermore, the nitazenes are highly lipid soluble, indicating rapid absorption and a distribution that favors the lipid rich CNS. This is exemplified by their lipophilic Log P range of approx 4.1 to 5.1, highlighting a pronounced preference for nonpolar environments. The nitazenes have greater lipid solubility than fentanyl, which possesses a Log P of 4.05.
A comprehensive understanding of the acid-base properties and lipophilicity of these molecules is crucial for elucidating their pharmacological behavior. Their dual acidic and basic character allows for interactions in diverse environments, while their high lipophilicity facilitates penetration through biological membranes, contributing to their potent CNS-mediated effect.
NITAZENE CHEMISTRY
Of the variety of routes to benzimidazole derivatives, the most popular are modifications of the classical acid-catalyzed cyclocondensation of 1,2-phenylenediamine.derivs (first devised in the late 19th century). The Ladenburg-Phillips reaction is a versatile and efficient method for synthesizing benzimidazoles. It involves the condensation of an o-phenylenediamine with a carboxylic acid, ester, acid chloride, or anhydride, followed by cyclization. This reaction was first reported in the 1870s and has since been used to prepare a wide variety of benzimidazoles with different substitution patterns. Carbonyl equivalents such as carbonitriles, imino-ethers, or amidines can also be used. The reaction is catalyzed by HCl, polyphosphoric acid or boric acid. The Weidenhagen reaction can be adapted using Cu(II)-mediated oxidative cyclocondensation to prepare benzimidazoles.
Synthesis of Nitazenes:
[For a full review of nitazene synthetic methodology, see the full version of this article at Patreon.com/Oxycosmopolitan]
-------------------END OF PART I-----------------
To read the full version of this article, visit Patreon.com/Oxycosmopolitan

I got a Rachel Reinert coloring book for Christmas and it has become my new creative obsession. Coloring is so soothing! So far I have the Rachel Reinert (easily my favorite) botanical wonderland book, and then botanical escapes, vintage botanicals, marvelous mushrooms, and medicinal plants. I didn’t realize when ordering the latter three that the paper would be so thin (or double sided printing in the case of medicinal plants and botanical escapes). I learned to use blotter paper inbetween to prevent bleed through.
I’m looking for something similar to Rachel Reinert, as well as thick paper mandalas, flash tattoo designs, botanicals without shading, mushrooms, wildlife, things without anthropomorphic elements like people and houses. I know that’s quite the range so send me your suggestions and bonus if they’re on Amazon! Photo of a poppy from vintage botanicals that I recently colored while learning how to blend my new alcohol markers. Thank you 🥰

Hello and welcome back to SAR! I have written and rewritten this post a few times now and I think I have landed on a format I am happy with. When we talk about the impact of medicine on history its important to get the context right, and I think I have found a way to talk about our topic. So what is it? No chemical is more important to the world of medicine than Opium, okay maybe Penicillin, but today we will say its Opium. Principally an analgesic (anti-pain), the Opium Poppy allowed for humans to take away pain in great degrees and further development on the natural chemicals has opened up surgery and post-op recovery. While we tend to look at the recent Opioid Epidemic as the only issue regarding Opiates, history reveals to us a very similar precursor. Also please head over to u/jtjdp post about morphine derivatives here! She does an amazing job explaining the higher level concepts of medicinal chemistry that I just wouldn’t do justice. Alright, enough quibbling, let’s get to the good stuff.
Disclaimer: this post is not designed to be medical advice. It is merely a look at the chemistry of medications and their general effect on the body. Each person responds differently to therapy. Please talk to your doctor about starting, stopping, or changing medical treatment.

How Much do you Know About Pain?

To be alive is to feel pain, and emo sentiments aside, this is one of the biggest biological properties of the central nervous system. When you think about it, how does the body take external stimuli and allow you to recognize it? The answer is the sensory nervous system which is responsible for sensing many different types of stimuli: temperature, pressure, pain, and chemicals. These sensory neurons carry the information from the extremities and transmit it up the spinal cord into the brain for processing. From there the brain alerts you to the issue allowing you to correct whatever problem is causing the pain. Let’s take a look:
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• We call these receptors Nociceptors and activation of these neurons in the periphery leads to a signal being sent towards the spinal cord. Those peripheral nerves eventually complex with the Dorsal Horn of the spinal cord and interface with the central nervous system to transfer the pain signal. This signal is then sent Ascending to the Thalamus where the pain signal is recognized and initiates a response (such as pulling your hand away from the hot stove). But that’s not the full story, the brain also sends signals back down Descending to modify the incoming signal and dampen it. Its this modifying that makes pain fade over time when you aren’t focusing on it—otherwise the brain would be overwhelmed by the repetitive signal and continuously think injury is still happening. Now let’s divide this process into its two parts, first up the Ascending pathway.

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• As the Action Potential travels from the periphery towards the Spine it causes the influx of Calcium into the Presynaptic Neuron. This neuron is what carries the original signal to then transfer into the Spine for further traveling. Eventually we reach the Synapse where the finger-nerve and spine meet and we get the transfer of information via Neurotransmitters. In this case, two chemicals are released: Glutamate and Substance P (which literally stands for Substance Pain). Glutamate will activate two receptors (AMPA and NMDA) which are Excitatory and stimulate the continuation of the pain signal up to the brain. Substance P activates the NK1 receptor which enhances the frequency of the pain signal (the throbbing) and the intensity of the pain burst. So to simplify, Glutamate allows the signal to be passed up to the brain but depending on the strength of the original pain signal more or less Substance P is released which modulates the strength and attention-grabbing nature of it. Okay great, we sent the pain pathway up and it will get processed in multiple different parts of the brain. But the brain can’t have that signal stinging it so it must send information back down to dampen that pain signal. This is where that aforementioned Descending pathway comes in. Above you can see how the blue line reaches down out of the brain and back into the spine to turn ‘off’ the signal. This is the basis of Analgesia or pain relief.

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• Okay so now we have to divide the action of the Descending pathway which acts to dampen and modulate the original signal coming into the brain. Now, normally at rest this Descending neuron is inhibited so any fresh incoming signal is not inhibited from the get go but once that pain signal does come in, we get the good stuff! In response to pain the brain releases substances called Endorphins which activate the mu Opioid Receptor (MOR) located on the Descending pathway. Now MOR are inhibitory in nature so they are inhibiting the inhibitory resting state of neurons, or in other words, are allowing the Descending neuron to activate. And this is an important fact to recognize, Opiates do not inhibit pain, they inhibit the physiology of the nervous system that prevents modulation of the pain signal.
  • Once the inhibition is inhibited, the Descending neuron is free to release two neurotransmitters onto the nerve that was carrying the original pain signal. Both Norepinephrine and Serotonin are released to activate their respective receptors which inhibit the release of Substance P and Glutamate thus decreasing the incoming pain signal. Likewise MOR receptors are found directly on the incoming nerve and further prevent the release of Glutamate and Substance P as well as being found on the Ascending neuron preventing the activation of the NMDA/AMPA and NK1 receptors. The result: dampened incoming signal and decreased pain sense being sent to the brain.

The Stars Align in the Shape of a Poppy

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To start our story about Opiates we need to turn to the great precursor—Opium. Opium itself is not a chemical but rather a really thick liquor (called latex) that contains a high concentration of Morphine (and some Codeine). There are 38 species of Poppy plants but only two produce Opium is great enough supply that it is worth farming them and humans have been cultivating these varieties for as long as we have known about the plants. When humans settled into Mesopotamia (near modern day Iraq), Poppies were one of the few plants grown in plots as large grain or vegetable fields (meaning that they were thought of as valuable as food). Throughout the Greek age of medicine (pre-500 BCE) through the Islamic medicinal revolution (500 BC-1500 AD), Opium was a major component of treatment, assisted suicide, and poison. In fact its through the rise of the Muslim Caliphates that we see the export of Opium to other parts of the world, especially through the Mediterranean Sea once the Crusaders return. Opium trading to the East via the silk roads was an almost continuous affair since time immemorial and Pakistan was a major growing area for the Eastern Poppy trade.

• By the time after the Crusades (11-13th centuries), we start to see the West’s fixation on Opium. For many reasons Europe didn’t develop many psychoactive plants to the same degree as more humid/hot climates like Africa, the Middle East, and India. This is why the importation of Opium (and also Marijuana) was such a trade commodity and staple in the development of Western medicine. During the Renaissance and the revival of Greek philosophy we start to see the re-fascination with Opium and by the 1600s we see merchants importing Laudanum into Europe for recreational and medicinal use. The standard use of Tincture of Opium (which is Opium dissolved in ethanol, a DEADLY combination) was a particularly favorite preparation which was prescribed to the lowest day-worker all the way up to kings.
  • The importation and use of Opium exploded in the late 1700s once the British conquered a major Poppy growing region of India. This region (western India and most of Pakistan) was originally slated to grow cotton like the American colonies but the region wasn’t wet enough to sustain the plant—it could however grow copious fields of Poppy plants to create Opium. Throughout the 18th century the British Raj became the largest exporter of Opium to Europe and after the discovery that Mercury and Arsenic may not be safe, Opium took over their duties. By 1780 almost all major remedies incorporated the use of Opium in some capacity and with the huge supply, it was incredibly cheap.

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• Poppy wasn’t only important to the British for its medicinal properties but also to bolster the huge amount of loss they were incurring in global trade to one trade partner—China. After she made contact with China in the mid-1500s, Britain starting to import HUGE amounts of tea as the Brits became literally addicted to the substance. By 1800 a full 15% of the ENTIRE British Empire’s revenue was being spent on importing tea, that’s 30 million pounds per YEAR, leading to a massive trade deficit. This means that more money was being sent to China literally enriching a foreign country while the British public was getting their fix on the black stuff. Oh and just in case you think things haven’t changed, Britain still accounts for 42.6% of the world’s tea consumption—seriously Brits, ever heard of coffee? Anyways, all this money leaving the British economy to be spent on non-Empire sustaining commodities was a major national security risk for the British. It would be different if they were importing gunpowder like the Dutch were or Silver as the Spanish had but literally they were consuming the riches they were spending the money on.
  • Remember too that the British were not in the best position by the turn of the 19th century—they had just lost their colonies in the Americas, involvement in the Napoleonic Wars killed a generation of men, and the push to develop industries over public health led to a focus on fast growth rather than smart growth. One of the results of the Napoleonic Wars was the British occupation of the Island of Java which developed a very potent Opium which was traded with Chinese merchants regularly. Soon British merchants realized they could rebalance the trade deficit by selling Javanese Opium into China but the small island was unable to produce enough Poppies to meet the demand. So Britain turned to another one of its colonies, India.

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• India by the end of the 1700s was a bit of a challenge. The British hold on the subcontinent was firm but they couldn’t grow the cash crops they wanted. Indian cotton was nothing compared to Egyptian or Southern American (i.e. Virginia/North Carolina/Georgia) cotton and the Indian tobacco was known for being bitter. But by the 1770s the British government realized that Poppy was an easy crop to grow and the demand across the border with China was an easy market; British traders brought their cargo to small islands off the coast of China where it was sold for silver. Initially the Chinese didn’t mind the sale of Opium in their territory—when the British traders collected the silver from the sale they would almost immediately use it to buy Chinese goods, thus driving tax revenue for the Chinese government.

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• But if you buy Opium, people are going to use that Opium. By the 1810s all trade with foreigners was restricted to just one port, Canton, and slowly the city started to develop a habit for the drug. The use of mind altering substances was curtailed pretty quickly for hundreds of years in China—the Ming Dynasty banned tobacco in 1640 and the Qing banned Madak (a powdered Opium containing tobacco) was similarly banned in 1729. But by 1790 more and more Chinese citizens were becoming addicted to the substance; what started as a recreational drug slowly became a crippling addiction that took hold over Canton. For a rigid society, the crippling Opiate addiction was a moral corruption for the Qing government and forced them to curtail Opium importation in 1780 and then an outright ban in 1796.

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• Knowing just how devastating the Opium was having on the inhabitants of Canton, as well as how it spread further inland, British merchants kept peddling their drug. Older ships with larger hulls were converted into floating warehouses and parked just outside of navigable waters. Once set up, Opium smugglers would pull up, purchase the Opium and avoid any oversight by the Chinese government to prevent the sale of the drug. Following their mother country, American merchants started to sell Turkish Opium, an inferior variety, at a much cheaper rate leading to drug peddling competition with more and more tons of Opium being sent into China. This drove down the price of Opium considerably which ultimately increased the demand.
  • This demand eventually led to reversal of trade, meaning that more silver was leaving China to pay for Opium than the British were using to pay for Chinese goods. American and European traders could show up in Canton with holds full of Opium, sell it off for a profit, and then make a tidy silver profit to bring back to Europe. Likewise the importation of cheap machine-made cotton, furs, clocks, and steel into China driving down domestic profits.

Let’s Look at the Drugs a Bit

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Stepping away from the history a bit, let’s introduce the Family. Okay so we understand how pain is sent to the brain and how it modulates but there is so much more to the mu Opioid Receptor and that’s not the only kind of Opioid receptor that we have. The two most clinically useful receptors are the Mu and Kappa Opioid Receptors (KOR) because they result in analgesia but there is a Delta Opioid Receptor (DOR) that is worth mentioning. The majority of the Opiates that we know and love are Mu agonists but there are some very interesting Kappa agonists that are worth mentioning as well.
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• Above is a chart that shows the binding affinities of select Opiates to the Mu receptor. The smaller the number is, the more tightly they bond. Now affinity is different than potency—potency is a measure of how much drug (in g) is required to produce the same effect. So even though morphine has a higher affinity than fentanyl, fentanyl has a MUCH more potent effect (which is why it can be so dangerous, you only need a little). Now many of the opiates cause the same effect so I want to spend more time on what makes them all so different:
• First up we have the 5-Ring Morphinians which are derived from the natural product Morphine. These structures have 5 component parts: an aromatic benzene ring (A), a completely saturated bridge ring (B), a partially unsaturated ring with an alcohol attachment (C), a piperidine heterocycle above the rest of the structure (D) and finally a ether linkage between the top and bottom of the structure to keep it fairly rigid (E). Truthfully we are only going to focus on two locations—firstly the top alcohol (red circle) can be methylated to form Codeine, a natural Prodrug of Morphine. A Prodrug is one that is biologically inactive but goes through an initial metabolism once ingested that makes it active.

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• In fact it’s this initial metabolism of Codeine that makes it very interesting. In order for Codeine to exert any pain relief it needs to be converted to Morphine which actually exerts the desirable properties. This is done by the liver enzyme CYP2D6 which is a pretty minor pathway for Codeine—only about 10% of the Codeine is actually converted to Morphine to have some action. Because of this 2D6 dependent pathway we have to be careful about administering drugs that might inhibit the 2D6 pathway because that would mean we are preventing codeine from being active. Drugs like Fluoxetine (Prozac) and Paroxetine (Paxil) are strong 2D6 inhibitors and so if we administered Codeine to someone taking this drug they’d never get any benefit from the Codeine. In addition there are genetic/ethnic differences that pharmacists can account for such as 2D6 activity. If you are someone with very little 2D6 activity then you would also not convert Codeine to Morphine and thus get no action from the drug—this may be a reason why some people say Codeine doesn’t work for them. Another reason could be that they are Rapid Metabolizers and quickly convert the Codeine to Morphine and thus get a massive hit quickly after ingestion—in that cause you’d need a much smaller dose than another person for the same effect.

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• A different drug that is the opposite of Codeine is Hydromorphone (Dilaudid) which has a Ketone on ring C. This ketone and the lack of the double bond on this ring increases the lipophilicity of the drug and increases its ability to penetrate into the brain and thus have a greater effect. In fact Hydromorphone is 5-10x more potent than Morphine due to its greater ability to penetrate into the brain and increased receptor affinity for the mu receptor. Because the A ring OH is not capped with a methyl group, we don’t need to rely on 2D6 to metabolize Hydromorphone into an active drug form which again increases the activity of this drug compared to Codeine.
• So combine these two structural changes—the capped OH on ring A as seen in Codeine and the increased affinity found with the ketone in Hydromorphone and we get Hydrocodone (Norco, Lorcet). Well in this case you’d get a drug that has very good affinity for the mu receptor (better than codeine) BUT is still reliant on the small 2D6 pathway for activation (worse than morphine). In this regard only about 10% of Hydrocodone is active at a time. We can see this effect in the relative doses for equivalent effect: to match the effect of 30mg of Morphine, we’d need only 7.5mg of Hydromorphone (more active) but need 200mg of Codeine (less active).

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• This brings us to our last drug of this class, Oxycodone which has a special OH group found on Ring B. What you’ll notice is that Oxycodone has that capped OH on ring A so it requires metabolism through 2D6 just like Codeine and Hydrocodone. When it is uncapped it becomes Oxymorphone which has 3 times as much effect as Morphine BUT that extra OH makes Oxycodone an exclusive Mu receptor agonist. Unlike the other drugs which may go to other receptors causing side effects (more on this later).

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• Next up I want to look at some Mu opioid receptor Antagonists or those than inhibit the function of the opioid receptor. Looking at the first two drugs, Naloxone and Naltrexone, we can see that they have the structure similar to Hydromorphone so they would have incredible brain penetration and affinity for opioid receptors BUT they contain that funky Nitrogen tail. Now normally there is a short methyl tail that is required for the function of Morphine but by adding a bulkier tail the drug is able to fit inside the receptor but prevent activation. What’s most important about these two drugs is that they have much more affinity for the receptor than other opiates. We can see this effect in the graph above: when no Naloxone is present, Fentanyl occupies the opiate receptor about 75% of the time. But as soon as Naloxone is administered that number drops swiftly (within minutes)--this is because Naloxone has a higher affinity for sitting in the receptor than Fentanyl. Think of it like the bully Naloxone coming up and pushing the poor defenseless Fentanyl off the swings so the bully can play on it (except in this instance Fentanyl is causing an overdose and we need to save someone’s life).

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• Buprenorphine is similar but it is a Partial Agonist instead of being a full antagonist. Buprenorphine is not a 5-ring Morphinian byt a 6-ring Oripavine that has a few different modifications. The biggest additions is that it has the bulky Nitrogen tail found in full Antagonists but it has this funky C ring tail which fights the antagonism. The result is a tug of war between the antagonism of the Nitrogen tail and the agonism of this new C-ring tail resulting in Partial agonism—so if you took Buprenorphine you’d notice a markedly decreased pain relieving ability but importantly there is a ceiling effect, its much harder to overdose on Buprenorphine than other full agonists. In addition in the second graph we can see that Buprenorphine has the greatest affinity for the receptor than our other agonists which prevents someone from taking a more potent opiate while taking Buprenorphine. In this case the bully is already sitting on the swing and scaring away the other kids thus preventing them from having a turn (and potentially causing an overdose). This does mean that if someone was taking a more potent drug (like Fentanyl) and then took Buprenorphine, it would cause withdrawal just like Naloxone or Naltrexone.

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• Speaking of withdrawal, let’s take a look at how that happens. Remember that the pain signal is caused by the activation of AMPA and NMDA receptors from the peripheral nerve. AMPA is a type of receptor called a G-Protein Coupled Receptor or GPCR which in this case is linked to an Excitatory G-protein which leads to the activation of the nerve. When AMPA is activated, the G-protein (Ga) activates an enzyme called Adenylate Cyclase (AC) which increases the production of pro-activity cAMP—or in simpler terms—when AMPA is activated, it leads to an increase in levels of pro-pain molecule cAMP. The Opioid receptor is also a GPCR but it is linked to an inhibitory G-protein which prevents the action of Adenylate Cyclase and thus leads to a decrease in cAMP levels. So Opiates prevent pro-pain cAMP signaling from continuing.
  • In the second graph we can see how tolerance forms. Initially (A), Adenylate Cyclase and cAMP levels are not affected by having opiates even though their ability to push along the pain signal is blocked. After a few hours, the leftover cAMP is degraded and cAMP levels start to drop significantly (B). In response to these levels going down, the activity of Adenylate Cyclase starts to increase and increase (C) which raises the level of cAMP. This rise in Adenylate Cyclase activity opposes the action of the opiate which necessitates the need for increased doses of Opiates and is why tolerance forms. As sustained inhibition of Adenylate Cyclase continues, the body upregulates Adenylate Cyclase activity to create more cAMP and to combat this we increase the dose.
  • Now what if after years of taking an Opiate we suddenly administer Naloxone, an Opiate antagonist. Well after weeks to months of taking an Opiate, the level of Adenylate Cyclase activity is WAY above baseline. When you administer the antagonist, suddenly Adenylate Cyclase is able to produce a TON of cAMP that normally is blocked which leads to a MASSIVE amount of downstream signaling. The result is intense nausea and vomiting, stomach cramps, fever, anxiety, insomnia, and cravings. Thankfully the withdrawal process ends after about 72 hours but is one of the worst experiences someone can go through which is why proper down-tapering of Opiates is extremely important.

A Change in Trade Policy

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Oh, you’re still here. Neat! So by the 1820s the Qing dynasty was running into many problems regarding Opium. Firstly they needed the Opium taxes to fund their efforts to put down the White Lotus Rebellion and retain power. But after almost 30 years of trade the effects on Chinese communities could not be ignored along with local officials operating under the imperial trade department, the Hong, profiting from bribes to allow Opium. Regardless of initial efforts things were getting out of hand for the Qing government. In 1800, about 4000 chests of Opium or 560,000 pounds entered the country but by 1830 that number exploded to 20,000 chests or about 3 million pounds. But more than the amount of Opium actually entering the country was the incessant rudeness of the British government to open trade.

• One of the “problems” for the British traders was how clamped down trade was with China. By 1800 all trade was limited to just Canton and the Hong was a strict master of trade. Foreigners were not allowed to appeal decisions made by the Hong and only Chinese traders could sell goods further inland than Canton. Traders chafed against this extreme oversight and sent hundreds of letters to the Hong requesting special dispensations which were summarily denied. Things changed significantly in 1834 when the Chinese trade was de-monopolized away from the East India Company allowing any private trader to get involved in the Eastern trade.

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• In August of 1834, the British sent Lord William John Napier to Macau as superintendent of Chinese trade with the explicit order to follow all Chinese regulations. Thinking he knows best, Napier decided that the restrictive Chinese trade system was too restrictive and sent a letter to the Viceroy of Canton. This was unheard of—NO foreign traders were allowed to speak directly with Chinese officials and the Viceroy refused to accept it. So why not double down by ordering two British ships to BOMBARD two Pearl River forts as a show of force? Luckily Napier died of Typhus almost directly after else it would have resulted in a full blown war.
• In 1839 the Qing government appointed Lin Zexu as the Opium czar to completely eradicate the Opium trade from China. Lin banned the sale of Opium in China completely, set up rehabilitation centers for those affected by the drug, and put addicts to work to distract them while detoxing. Lin demanded that all Opium supplies must be surrendered to Qing authorities and any Chinese citizen disobeying the order would be punishable by death. He even went as far as closing the Pearl River Channel, trapping British traders in Canton and seizing their Opium warehouse stockpiles.
• The replacement for Napier was Admiral Sir Charles Elliot who protested the seizure of the Opium stockpile but knew that they could do nothing. He ordered all Opium ships to flee and prepare for battle which caused Lin Zexu to beseige a group of traders inside a Canton warehouse. Elliot convinced the traders to cooperate with the Chinese government and surrender their stock, saying that the British government would compensate for the lost Opium (which he had no authority to do). During April and May 1839 the British (and American) traders to surrender 20,000 chests of Opium which was burned for three days outside Canton. Following the burning, trade resumed to normal except no more Opium was allowed. Like many other instances of the government removing legitimate sale of a drug, the black market increased markedly.
• In July 1839 a new scandal rocked the British-Chinese trade system; two British sailors became drunk and beat a man death outside of his village. In response, Superintendent Elliot arrested the two men and paid compensation to the villager’s family for the loss of the man but Elliot refused to hand over the sailors to the Qing government. Lin Zexu saw this as a blatant disregard for Chinese law—afterall traders needed to understand that they can’t just come to China and violate Chinese law as they saw fit. Elliot offered to hold a trial on a British ship in front of Chinese officials to show that the men would not get off free. This incident would start the smoldering.
  • On September 4th, Elliot sent two ships to Kowloon to buy food and provisions from Chinese peasants. While approaching the harbor, three Chinese war junks gave permission to the two British ships to trade but that permission was rescinded by the commander of Kowloon fort. Elliot fumed against the slight and said that if the British were not allowed to trade by 3pm, he would fire on the fort. 3pm passed and the British opened fire on the fort causing the Chinese junks to return fire. The fighting continued for 7 hours until nightfall and Elliot had to prevent the British officers from pressing the attack, thus ending the Battle of Kowloon. Having driven off the Chinese ships, the British purchased the supplies they needed while the Kowloon commander claimed that both ships were sunk and 50 British sailors killed.
  • The reaction in Britain was about as much as you expect. Prime Minister Palmerston sent out letters to the Governor General of India to prepare marines to invade China and another letter to the Chinese Emperor telling him that Britain would send a military force. He sent a letter to Superintendent Elliot to set up a blockade on the Pearl River and capture Chusan Island. He also instructed Elliot to accomplish the following objectives:
    • Demand the respect as a British envoy from the Qing Government.
    • Secure the right for British law to be doled out on British subjects
    • Get recompense for destroyed British property, especially the illegal drugs that they destroyed
    • And most important, End the Canton System thus opening up China to free trade for the first time, ever.

Alright this is where we will leave things off for now, on the brink of war with China. Stay tuned!

I’m big on on growing and preparing food in more local and sustainable ways, and it’s hard to cook a myriad of recipes without milk. However, there are a lot of reasons people can’t or won’t use dairy milk. Everything from the amount of abuse and environmental impact of the 10s of millions (low estimate) of cows raised in CAFOs (Concentrated animal feeding operations), to the high concentration of Phthalates (endocrine disrupting chemicals added to plastics to make them more flexible) in milk from contact with tubing in milking machines (Phthlates contamination if actually really low in hand milked cows), to the fact that a single dairy cow takes about an acre but usually closer to 2 worth of forage to feed (which most people wanting to raise there own food simply do not have), to trying to lower saturated fat and cholesterol intake, the fact that 65% of the global population has some degree of lactose intolerance, etc. That’s without even getting into the recent trend of drinking raw milk and how quickly people forgot how many people that used to make sick and kill through disease like E. Coli, brucellosis, Salmonella, Listeria, typhoid fever etc.
I drew this poster but stayed away from the common milks you can buy in stores like soy, rice, coconut, oat and nut milks and instead focus on milk alternatives you can grow or forage easily instead. I have no issue with those, but feel like the average person is at least already aware of them.
For the pumpkin, poppy, chia and sunflower seed, peanuts and hackberries, the recipe is basically the same. Soak seeds in water, at least 4 hours but preferably overnight. drain the water from the seeds and rinse them thoroughly. Drain the seeds and combine them in a blender with 4 cups water per 1 cup of seeds. (You can adjust depending on desired consistency.) Add sweetner and/or vanilla and a pinch of salt if desired to taste. Strain through a fine-mesh strainer or cheesecloth. The solids you can use in baked dishes, soups or soups or as the base of veggies patties. (Maybe not the sunflower seeds unless you already like stabbing your gums eating the shell.) Finally, chill in the fridge where it will last 3-4 days if you don’t want to use it right away. For potatoes, peel and boil then follow the same recipe as above. For bananas, simply blend with water until your desired consistency. For quinoa, similar to making oat milk, boil in water. Let simmer until fully cooked. Then follow recipe as above. For cattails, clean and remove the outer layers of the tuber to reveal the starchy portion. Grate or finely chop the cattail rhizomes into small pieces. Add the rhizomes and about 4 cups of water for every 1 cup of grated rhizomes to a bowl, and let it sit 10-15 minutes so the starch separates. Add sweetner and/or vanilla and a pinch of salt if desired to taste. Strain through a fine-mesh strainer or cheesecloth. Cattail milk may have a somewhat slimy or mucilaginous compared to dairy. If you’re not a fan of Okra, you won’t be a fan of this. For corn, the kernels can be blended with water and strained or you can run a knife down the dekernaled cobs to collect a linguist referred to as corn milk.
Poppies (Papaver somniferum) most well known for containing alkaloids such as morphine and codeine, which are powerful pain-relieving compounds, it is also edible with the flowers being consumable and the seeds being a common ingredient in many dishes. The morphine and codeine are concentrated in the sap, so it poses little risk to consume the flowers or seeds, but the leaves and stems are not typically consumed. The seeds can be soaked and blended to make a milk alternative.
Pumpkins (Cucurbita pepo) the fruit is actually a berry, and every‪ part of the pumpkin plant is edible. ‬ Flowers, leaves, seeds, fruit. One of the oldest domesticated plants going back as early as 7000 bc. The seeds can be soaked, combined with water in a blender, and strained to make a milk alternative. The solids can be used as a soup stock or to make an alternative tofu. The word "pumpkin" originated from the Greek word "pepon," meaning "large melon” while the indigenous called them squash whichcomes from the Narragansett Native American word askutasquash, which means “eaten raw or uncooked.” It had spread there from where it was bred in the Andes
Potatoes (Solanum tuberosum) The word "potato" originated from the Spanish term "patata," which was derived from the Taíno of Quisqueya (Hispaniola) word "batata." In Quechua, which is still spoken by many people in the Andean region today, the potato is called "papa." In Aymara, another indigenous language spoken in parts of the Andes, the potato is known as "thaya." It is one of the most calorie dense crops, and other than being low in proteins and fats, it could work on its own as a healthy survival food and history even demonstrates this in the increase in health it gave to the Irish who were systematically deprived of other foods by the English.
Peanuts (Arachis hypogaea) although called peanuts, peanuts aren’t actually nuts but legumes and the peanut actually grows below ground from the roots. They originated in Bolivia and Peru as far back as 7,000 years ago. Also, interesting to note they were a traditional companion plant for corn, and being a nitrogen fixing plant would make a good addition to a three sisters planting.
Hackberry (Celtics spp) There are around 60 different species of hackberry trees found around the world, with the most common species being Celtis occidentalis (common hackberry) and Celtis laevigata (sugarberry). One notable feature of hackberry trees is their unique bark. It is grayish-brown with prominent cork-like warts or ridges, giving it a distinct appearance. They have small, round fruits known as drupes. These edible fruits are typically orange-red to dark purple when ripe and have a sweet, sugary taste.
Hemp (Cannabis sativa) ‪The plant has a strong and fibrous stalk that can be processed into different materials, including fibers, textiles, paper, and construction materials like hempcrete. It was domesticated in a part of Asia referred to as the Hemp belt that includes parts of modern day China and Mongolia. The seeds are edible and can be soaked and blended to make an alternative milk, and the leaves and flowers are edible but could add a psychoactive effects to food though most hemp,is bred to have very low levels of CBD and THC.‬
Chia (Salvia hispanica) A staple food in ancient Mesoamerican civilizations, such as the Aztecs and Mayans. The word "chia" even comes from the Mayan language, meaning "strength." While they are usually known for their seeds, the leaves and flowers are also edible. The seeds are an excellent source of omega-3 fatty acids, fiber, protein, antioxidants, and various vitamins and minerals, including calcium, phosphorus, and magnesium.
Corn (Zia mays) was bred from teosinte in Central America from a wild grass into the plant with large cobs of multiple kernels we know today over hundreds of generations. There are literally thousands of varieties bred for a variety of local conditions.
Quinoa (Chenopodium quinoa) is a staple food cultivated for at least 5000 years of the plant domestication powerhouse that was the Andean region that also gave us potatoes, tomatoes, and chilies. The whole plant, not just the seeds are edible like it’s cousins, lambs quarters and amaranths. It is also a source of all nine essential amino acids, which is rare for plants. It exhibits remarkable biodiversity, with hundreds of varieties and colors available.
Sunflower (Helianthus spp) ‪First domesticated in Central America at least 30000 years ago, every part of sunflowers are edible and were a huge part of the Eastern Agricuktural complex and often uses as a fourth sister in a three sisters planting of corn beans and squash. The seeds, the flowers, the leaves, the roots, the stalks. Sunflowers exhibit a unique behavior known as heliotropism, where their flower heads track the movement of the sun across the sky during the day. ‬
Cattail (Typha spp) the entire plant is edible. The starchy rhizome can be eaten raw, used like a potato, or soaked in water to separate the starch and use that to make a milk alternative. The pollen can be collected and used as a spice or flour alternative, and the young shoots can be eaten raw and taste similar to cucumber. Since cattails grow in water, extra care must be taken not to harvest from polluted areas.
Banana (Musa paradisiaca) ‪Domesticated from Musa acuminata and Musa balbisiana, which are native to Southeast Asia, thousands of years ago to remove the large seeds and produce larger sweeter fruit. They began being propagated vegetatively, which led to commercial bananas being exact clones and heavily susceptible to disease, like Panama disease that nearly wiped out the Gros Michel. Often thought of as a tree, the plant actually contains no lignon and is instead the worlds largest herbaceous plant.‬
For the pumpkin, poppy, chia and sunflower seed, peanuts and hackberries, the recipe is basically the same. Soak seeds in water, at least 4 hours but preferably overnight. drain the water from the seeds and rinse them thoroughly. Drain the seeds and combine them in a blender with 4 cups water per 1 cup of seeds. (You can adjust depending on desired consistency.) Add sweetner and/or vanilla and a pinch of salt if desired to taste. Strain through a fine-mesh strainer or cheesecloth. The solids you can use in baked dishes, soups or soups or as the base of veggies patties. (Maybe not the sunflower seeds unless you already like stabbing your gums eating the shell.) Finally, chill in the fridge where it will last 3-4 days if you don’t want to use it right away. For potatoes, peel and boil then follow the same recipe as above. For bananas, simply blend with water until your desired consistency. For quinoa, similar to making oat milk, boil in water. Let simmer until fully cooked. Then follow recipe as above. For cattails, clean and remove the outer layers of the tuber to reveal the starchy portion. Grate or finely chop the cattail rhizomes into small pieces. Add the rhizomes and about 4 cups of water for every 1 cup of grated rhizomes to a bowl, and let it sit 10-15 minutes so the starch separates. Add sweetner and/or vanilla and a pinch of salt if desired to taste. Strain through a fine-mesh strainer or cheesecloth. Cattail milk may have a somewhat slimy or mucilaginous compared to dairy. If you’re not a fan of Okra, you won’t be a fan of this. For corn, the kernels can be blended with water and strained or you can run a knife down the dekernaled cobs to collect a linguist referred to as corn milk.

NeuroPure Reviews Reddit (2023 Update) Ingredients, Side Effects, Negative Complaints Where To Buy NeuroPure?

NeuroPure Reviews Reddit

NeuroPure Reviews Reddit

Getting up with oh-so-irritating and frustrating nerve pain? You are looking forward to a great day ahead, but your body’s nerves do not feel fresh and healthy. Are you experiencing injury-induced neuropathic pain as well? Well, there are hundreds of people out there feeling the same every day.
You might have by now tried several homemade formulas and market-brought remedies, medications from big pharmaceutical companies, tablets, etc., but the issue of nerve pain still remains.
There are several products and medications made synthetically available in the market which advertise to help you get rid of neuropathic pain. But, they can be harmful to your body due to the absence of natural ingredients and natural formulas in them.
To tackle such chronic pain and nerve-related issues, a health supplement is available in the market known as NeuroPure.
NeuroPure, as per its official website, is an advanced natural formula that helps relieve neuropathic pain and strengthens the nervous system. It can be consumed daily to increase your body’s ability to reduce nerve damage and tissue damage.
In this article, we will target every detail of the features, functioning of the NeuroPure formula, price details, money-back guarantee, benefits to your body, etc.
We start this NeuroPure review article by overviewing the article from the table given below.
Product Overview
Product Name
NeuroPure
Product Category
Dietary Supplement
Product Distributor
Premier Vitality
Product Form
Capsules
Servings Per Bottle
60
Serving Size
2
About The Product
NeuroPure is an oral dietary supplement that helps reduce nerve pain by tackling the toxic enzymes in your brain.Features Of The Product

• Natural Ingredients
• Advanced formula
• Plant-based
• Made in the USA
• Manufactured in an FDA-Approved and GMP-Certified facility
• GMO-free
• Keto diet-friendly
• No tolerance-forming
• Harsh chemicals-free
• Filler-free
• Toxin-free
• Stimulant-free

Key NeuroPure Ingredients

• Corydalis
• Passion flower
• Prickly pear
• California poppy seeds
• Marshmallow root

Intake Guideline
Consume two NeuroPure capsules daily – one in the morning and one before going to bed.
Key Benefits Of Using NeuroPure To Your Body

• Helps reduce nerve pain, and the discomfort caused due to it.
• Helps relieve stress, anxiety, sleep, depression, insomnia, etc.
• Helps eliminate harmful enzymes.
• Helps reduce oxidative stress and free radical damage.
• Helps tackle neuropathy and related issues.
• Helps reduce high cholesterol levels.

NeuroPure Pricing

• Buy one bottle at $69 per bottle + free shipping (30-day supply package)
• Buy three bottles at $59 per bottle + free shipping (90-day supply package)
• Buy six bottles at $49 per bottle + free shipping (180-day supply package)

Bonus Products
Two bonus products along with all the packages:

• Fat Burn Tricks – The Keys To Body Transformation
• The Complete Neuropathy Protocol

Money-Back Guarantee
100% satisfaction 60-day money-back guarantee
Where to Buy NeuroPure
Official website of NeuroPure

About The NeuroPure Supplement

NeuroPure supplement is a neuropathic pain relieving supplement that is made up of completely natural and plant-based ingredients.
It helps you reduce inflammatory pain with the help of its formulation designed by Chris Adams. The NeuroPure formula is designed to eliminate the toxic enzymes in your nervous system that are the root cause of nerve pain and neuropathy.
A few reasons why you are suffering from neuropathy and any related disease are stress in muscles and tissues, anxiety, depression, diabetes, inflammation, harmful enzymes in your brain, obesity, oxidative stress, etc.
These NeuroPure capsules are made up of top-quality natural ingredients completely free from any adulteration like chemicals, fillers, stimulants, etc. This formula is side-effect-free as well.
The NeuroPure product official website promises fast results for your body in just a few weeks of regular consumption.

What Are The Ingredients Used In NeuroPure To Help Alleviate Nerve Pain?

Here are the core ingredients in NeuroPure that make it work:
Corydalis yzernyi (syn. C. saccata) is an herb native to Europe and Asia, where it grows wild in moist places such as riverbanks and marshes. The plant contains several alkaloids, including tetrahydroharmine, harmane, norharmane, harmaline, harmine, harmol, harmalol, and harmaline. Corydalis species contain high concentrations of these alkaloids and are known to produce sedative effects when ingested orally. In traditional Chinese medicine, corydalis is used to treat insomnia, anxiety, depression, and chronic pain.
The active ingredients in corydalis are thought to be responsible for its analgesic properties. These include the alkaloid compounds harmane, norharmane, and harmaline. Harmane is believed to be the most potent compound in the plant, and may account for up to 50% of the total alkaloid content. Harmaline is also present in significant amounts in the plant.
Both harmine and harmaline are known to act as agonists at 5-HT2A serotonin receptors. This receptor type is involved in the modulation of nociception and antinociceptive activity.
In addition to its analgesic effect, corydalis has also been reported to possess anxiolytic properties. A recent double-blind placebo-controlled trial evaluated the efficacy of corydalis in treating patients with generalized anxiety disorder.
Patients were administered either corydalis or placebo capsules twice daily for 4 weeks. Results indicated that corydalis treatment resulted in statistically significant improvements in patient ratings of anxiety compared to those who received a placebo.
Passionflower is a perennial flowering vine belonging to the Passifloraceae family. Its common name comes from the Latin word “passio,” meaning suffering or distress. Passion flowers are native to tropical regions of South America, Central America, Mexico, and parts of Africa. They grow wild in tropical rainforests and along riversides.
Passion Flowers contain several types of alkaloids, including apomorphine, hyoscyamine, and scopolamine. Apomorphine is a natural dopamine antagonist which acts as a stimulant. Hyoscyamine is a tropane alkaloid similar to ephedrine. Scopolamine is a quaternary ammonium derivative of hyoscyamine. All three alkaloids are thought to contribute to the passion flower’s pharmacological action.
Passionflower is well known for its ability to relieve symptoms associated with nervousness and stress. It is often prescribed for people experiencing restlessness, tension, and anxiety. Studies have shown that passionflower can reduce feelings of anger, irritability, and frustration. It is also effective in reducing muscle spasms, tremors, and twitching.
Neuropathic pain results from damage to nerves and is characterized by burning, tingling, numbness, and/or electric shock sensations.
Passionflower has been found to be useful in relieving nerve pain. A study published in the Journal of Ethnopharmacology investigated the use of passion flowers in treating neuropathic pain.
The California poppy (Eschscholzia California) is an annual herbaceous plant in the Papaveraceae family. It grows wild throughout North America and Europe. The seeds of this plant contain high levels of the opiate alkaloids codeine and morphine.
Opiates are naturally occurring substances derived from opium poppies. Codeine is one of the primary alkaloids found in the seeds of the California poppy. Morphine is another major alkaloid found in these seeds.
Codeine is used medically to treat mild to moderate pain.
Marshmallow root (Althaea officinalis), also called marshmallow root, is a perennial herbaceous plant in the Malvaceae family. It is native to Eurasia and North America. In the United States, it is commonly grown in gardens. Marshmallow root contains the compound althea eaton, which is believed to help alleviate nerve pain. Altheaetin is structurally related to serotonin, a neurotransmitter involved in mood regulation.
A study published in the journal Phytotherapy Research compared the effects of marshmallow root extract versus placebo on patients with chronic back pain. The participants received either a placebo or 2 grams of marshmallow root extract daily for 4 weeks.
After completing the treatment period, the participants reported lower levels of pain than those who had taken the placebo. These findings suggest that marshmallow root may be beneficial in managing chronic back pain.
The prickly pear (Opuntia ficus indica) is an annual herbaceous plant native to the Americas. It grows in arid areas throughout North America, Europe, Asia, Australia, and New Zealand. In Mexico, it is commonly called “chaya” and is used as food.
Prickly pears contain various bioactive compounds such as polyphenols, flavonoids, anthraquinones, saponins, and sterols. Anthraquinones are glycoside derivatives of 1,4-anthracenedione. Saponins are steroidal glycoalkaloids that form soap-like lathers when mixed with water.
Sterols are cholesterol-like substances. Polyphenols include phenolic acids, flavonols, and proanthocyanidins. Flavonoids are a class of polyphenol compounds that includes flavones, flavonols, chalcones, dihydrochalcones, aurones, and isoflavones.

How Does NeuroPure Work? What Is The Scientific Evidence Behind The Working Of This NeuroPure Supplement?

NeuroPure dietary supplement works towards eliminating the toxic enzymes from your nervous system and brain that are the root cause of nerve pain.
It has been proven by scientific research that the three enzymes called COX-2, PGE-2, and MMP-13 are the root cause of neuropathy and other symptoms related to it. The NeuroPure support formula has anti-inflammatory properties that help to reduce neuropathic pain and oxidative stress. These three enzymes also cause inflammation and chronic pain that decrease the effectiveness of your brain and nervous system.
NeuroPure helps get rid of pain due to the combination of key nutrients like marshmallow root, prickly pear, passion flower, etc.
It becomes very important to improve the function of the nervous system to recognize the needs of the body and the harmful enzymes that affect it.
This is where the NeuroPure support formula helps you to improve the condition of the customers facing neuropathy and any related disease that could affect your day-to-day life and function.
The NeuroPure supplement formula helps support a healthy life due to these ingredients. These natural and plant-based ingredients have been scientifically tested and proven to provide certain health benefits to your body which we’ll discuss further in this article.
Passionflower possesses sleep-inducing properties in the NeuroPure dietary supplement. Its unique formula helps reduce the risks and impacts of insomnia on your health, thus also allowing your body to completely relax and calm down from all the stress and anxiety. According to a study done in 2020, it was found, based on clinical trials, that passion flower (Passiflora incarnata) may help treat some symptoms in neuropsychiatric patients.
Another study conducted on male adult Wistar rats found that the medicinal plant passion flower (Passiflora incarnata) extract can be considered an appropriate inducer of sleep. It showed a significant improvement in the total sleep time of the male rats.
Another ingredient used in the NeuroPure formula is marshmallow root. Marshmallow root helps relieve nerve pain, stress on nerves and muscles, and related health conditions. As per a study done on marshmallow root Althaea Officinalis L. (A. Officinalis), it was found that it has antioxidative and anti-inflammatory properties.
In animal studies, corydalis extract has shown antihyperalgesic and antinociceptive effects. A study conducted by Zhang et al. showed that oral administration of corydalis extract significantly reduced mechanical hyperalgesia induced by carrageenan injection into the rat paw.
Another study demonstrated that intrathecal injection of corydalis extracts produced dose-dependent inhibition of thermal hyperalgesia induced in rats by intraplantar formalin injection.
A number of studies have demonstrated the potential benefits of using prickly pear in managing chronic pain conditions. For example, one study showed that prickly pear extract was able to alleviate pain caused by osteoarthritis. Another study suggested that prickly pear could help manage diabetic peripheral neuropathy.
In a study published in the journal Neuropharmacology, researchers examined the effectiveness of California poppy seed extract in alleviating neuropathic pain. Participants were given either a placebo or a standardized extract containing 10 mg of morphine per gram of dried poppy seed. The participants took their medication orally once every 12 hours for 3 days.
After taking the medication, they rated their level of pain on a scale of 0-10. On average, the participants experienced a reduction in pain intensity after receiving the active drug. This indicates that California poppy seed extract may be helpful in treating neuropathic pain conditions.

Intake Guideline Of NeuroPure

As per the instructions mentioned on the back label of the NeuroPure bottle by the manufacturer (Chris Adams) of the product, you have to consume two capsules of NeuroPure daily – one capsule in the morning and one capsule before going to bed.
Taking NeuroPure regularly will help tackle the root cause of neuropathic pain and relieve it. Its continued use will hopefully eliminate the toxic enzymes in your brain.
In case of any query related to the intake of this formula, you can contact their customer support team.
The maker of the NeuroPure product have listed a few precautions to take care of before taking this neuropathy supplement-
Do not exceed the recommended dose of this formula. Consume it as per the back label of the product or as recommended by your doctor.
Discontinue usage of the NeuroPure supplement if allergic reactions like irritation, redness, itching, etc.
It is not recommended to use by a pregnant, lactating, or nursing woman without doctor consultation.
Do not use it if you are already on medications for any other health problem. In this case, consult your doctor first and use these capsules under his guidance and supervision.
Keep out of reach of children.

What Are The Benefits Of Using NeuroPure?

The NeuroPure dietary supplement offers the following health benefits irrespective of age and gender:

• Helps promote immunity and reduce the risks of diabetes.
• This formula helps deal with neuropathy and related issues.
• Helps reduce pain in your nerves by reducing the effects of the three enzymes.
• This formula is completely natural, so side effects are free and safe.
• Helps reduce inflammation and symptoms associated with it.
• This plant-based formula helps get rid of nerve damage causing three enzymes.

Where Can You Purchase NeuroPure?

NeuroPure can be brought directly from the official NeuroPure website.
The makers of the product do not sell it on any of the third-party platforms, so their official website is the only place to go if you want to buy it.
The bottle of NeuroPure, can be brought from the official website in any of the three packages mentioned below at discounted rates-

• Buy 1 NeuroPure Bottle at $69 per bottle + free shipping (30-day supply)
• Buy 3 NeuroPure Bottles at $59 per bottle + free shipping (90-day supply)
• Buy 6 NeuroPure Bottles at $49 per bottle + free shipping (180-day supply).

As you have already seen above, NeuroPure is available for purchase in three packages on their website.
So, after you choose any of the packages and place your order, you will be automatically covered by their full 60-day, 100% refund policy.
This means that if you change your mind at any time, or for any reason, you can just email their customer support team, and you will be refunded your entire money, no questions asked, which means there is absolutely no risk for you as a customer of the product after you purchase it.

NeuroPure Reviews – What Do The Customers Have To Say?

Looking at several positive reviews on NeuroPure, it becomes almost impossible not to believe that the customers are seeing results after using this product.
They have experienced an improvement in their body’s ability to bear pain in the nerves with the help of these miraculous capsules.
These capsules with a unique formula have even helped in case of chronic pain in your muscles and tissues.
This is not the only one, many suffering from neuropathy have dealt with the same thing of trying out tons of products and remedies from the market, but not even one was able to solve their problems and provide a solid full-proof cure to the same symptoms.
The reviews by hundreds of customers are proof of the claims made by the maker of this product.

Final Verdict – NeuroPure Reviews Reddit

Based on customer reviews, NeuroPure capsules seem to be completely worth it.
It promises reduced nerve pain and delivers the same. It treats the neuropathic pain caused by toxic enzymes and removes its root cause so that there is no chance of it returning in the near future.
So, if you are someone who has tried every possible medication and remedy out there but is still not able to cure pain in your nerves, then you might think of giving NeuroPure a try!

When Pizza Politics Meets Poppy Politics: The Hidden Legal Liability of Pizza Toppings

Thebacon vs. Thebaine

In the opioid analgesic industry, we have drugs such as Thebacon, or dihydrocodeinone enol acetate, which is a derivative of Thebaine.
​
Thebacon
Thebacon retains the 6-7 double bond of codeine, resulting in its lower potency compared to acetyldihydrocodeine, where the C-ring is fully saturated, leading to an energetically favored chair-formation of the cyclohexyl system (ring C). It also retains the 6-OH, in the form of the O-acetate. The O-acetate leads to a more lipophilic molecule compared to codeine and a drug with in vivo activity on par with morphine. The potency of thebacon is approx 0.8 x morphine.
​
Thebacon retains the 6-7 double bond of codeine, resulting in its lower potency compared to acetyldihydrocodeine, where the C-ring is fully saturated, leading to an energetically favored chair-formation of the C-ring. It also retains the 6-OH, in the form of the O-acetate. The 6-O-acetate combined with the 3-OMe ether enhances the lipid solubility of the molecule compared to the comparable morphine homolog. The in vivo activity of the 6,7-enol-acetate is on par with morphine (thebacon = 0.8 x morphine), while most codeine derivatives are ten times weaker than their free phenolic morphine counterpart. Introduction of the 6,7-enol-acetate provides resonance to the 4,5-epxymorphinan hetereocycle, which helps to explain the eight-fold activity increase from plain vanilla codeine.
If it weren’t for the obscurity of such nomenclature embarrassment, then ordering a pizza with pineapples and Canadian bacon (which is already faux pas; and offends my breakfast baconineapple) could become a statutory drug crime.
How many times have you ordered a “meat lovers special” from your local pizzeria and asked them to “Hold the Bacon”? If you truly loved meat, then probably never. Those wise to the entrapment-friendly tactics of law enforcement have developed a keen intuition (some of which is borderline divine) which helps these savvy swashbuckling swineophiles avoid LE dragnets and other legal consequences for "bacon-related crime," some of which are simply trumped-up on absurd premises.
If they were holding Thebacon for you, and your phone was the focus of a serious law enforcement investigation, i.e. it was being wiretapped, this could lead investigators to a wide ranging conspiracy involving late night visits by a pizza delivery driver known as “Big Papa John,” a consigliere known as Suge “(Diet) Tootsie Pop” Lite, who would inevitably finger you as the leading Don of thebacon empire: “El Chapo of the Pizza Crust”
If you’re more gung-ho about your pork derivatives and aren’t easily dissuaded by a 1%er Outlaw Meat Lovers-Motorcycle Lifestyle, then perhaps you won't be intimidated to fuck around with Felonious Pork Fritters. Beware of wide-ranging federal indictments for “Conspiracy to Distribute Controlled Pulled Pork Analogues.”
It could even lead to a proliferation of the underground opioid market. In this same manner, fenta-fried El Chapos could later abuse the legal tennant of “Pork Privilege” by simply converting to Islam or Judiaism and claiming KosheHallalkhic privilege: *If thebacon doesn’t fit into dietary law, then how can it be used to settle drug dealing law?*
The delivery of ***controlled bacon*** is not viewed as a laughing matter. And, if the bacon is serious enough, it can result in prison time.
If you are ever again faced w/ a “*Meat Lover’s Trio*” paradox: forced to choose between the tenants of pepperoni, sausage and bacon. *Please hold the pepperoni,* before messing w/ ***thebacon***.
If ***thebacon*** fits, you don’t acquit.
Don’t do the swine, if you can’t do the time.
I like it when you call me Big Papa…John’s. Put yo ham in the air, if you’re a bacon-playa.
Is it Dilaudid or Digornio’s?
\------------------------------------------------------------------------
***Saran Wrap v. Sarin Wrap***
The frequent confusion of plastic wrap (Saran) with nerve gas (sarin) is a tragedy that brand name marketers on the Sandwich wrap side of the misunderstanding could have done a better job of anticipating. The ensuing polymer-based political crises and the spillover into the Saranocialists and the Sarinihlist movements , has left an enduring and highly oxidized legacy.
“The Rise and Fall of Polyethylry”
Saran Wrap was invented in 1933 by Ralph Wiley. The nomenclature upon which the brand was named fell upon Wiley’s boss, who chose to name the wrap after his Wife and Daughter: Sarah + Anne.
The original formula used a polymer of [polyvinylidene chloride](https://en.wikipedia.org/wiki/Polyvinylidene_chloride) (PVDC), which was renowned for its impressive oxygen impermeability, self-adhesion, and all around Stickiness. The protective anti-oxygen-membrane was immensely useful to the preservation of meats from spoilage; its use to preserve both Canadian bacon and breakfast ***bacon*** made the film legendary and essential among the industry shotcallers.
In a controversial 2004 decision led by leading vegan authorities and the (free)-radical political-arm of the “National Saran Devinylization of PVDC” (acronym: “NSDAP”) the more politically expedient successor to the “Saturated Fat Commission,” PVDC was dropped by the Manufacturer in favor of low density polyethylene.
This preserved some of the properties, but sacrificed the legendary oxygen impermeability. Oxygen permeability increased nearly 3333-fold. From 0.6 in the original PVDC based polymer to 2000 cm3 μm m−2 d−1 kPa−1 permeability of the polyethylene based replacement.
Saran Wrapped sandwiches are a frequent paraphernalia associated with soccer moms.
According to “Helicopter Parent Press” the 2004 disenfranchisement of Saran Wrap oxygen-integrity has resulted in a move towards the Bacon, Lettuce, Mayo (BLM)-alternative known as the Sandwich Baggie. The oxygen permeability of these bags is lower than the Saran polyethel-switch. Leaving lettuce to wilt at the hands of radical oxidation.
This sparked widespread controversy in “consumer-brand based political circles.”
A cult of “wrapid (free)-radical opposition to the polyethylamorous wrap” has emerged as a growing outspoken minority.
Personally, I am sentimental for the Latter-Day Saran-Saints. Obviously, I could do without sister wife competition, and the increased premiums paid for “Polygamous Life Insurance.”
Otherwise their position seems to be based on sound politico-polymeric permeability. While the Polymer Proletariat may disagree, I am of the conviction that “Not all polymers are made equal.” Some serve a higher purpose than others. Some take out the garbage, others bravely defend our sandwiches against Romaine lettuce social-spoilage. Different roles for different petropolyamorers.
While PVDC was removed from the Saran-family long before I became the Petrochemical Industry’s “Shadow Commissioner on Tasteful Branding,” I’m a big proponent of reused bacon and less-excited about the proliferation of aerobic bacteria on my soon to be consumed, rewrapped deli meats.
The removal of Saran-based prophylaxis has resulted in the disenfranchisement of millions of soccer moms (whose ranks I’d gladly join if I could find a worthy stud farmer).
The 2004 election of Low-Density Polyethylene over the conventional PVDC has resulted in a schism of the Soccer Mom Caucus. Many radical party members have accused the industry of oxygen-barrier fraud.
An industry-backed propaganda campaign aimed at the hearts & minds of the outspoken opposition was themed “What’s safe for the pan, is safe for Saran.”
The (free)-Radical members of the Helicopter Parent Coalition adopted a counter-campaign entitled “Make Saran Safe Again.”
The more militant “Dads Against Polyethylry”movement changed their name to the the epic “*Saran Sirhan*.”
(Labeled by the Kenned family-owned Low-Density Polyethylene industry as the “SS”)
Sarin Wrap, a nerve agent, that finds few friends, esp in hotspots such as Northern Iraq and Tokyo Subways (where the sandwich meets the tracks) isn't as welcome in the environs of the suburban SUV as, lets say, PB&J, Cheez-Its and Frito-Lay. It’s nomenclature confusion with the pro-Saran movement has resulted in a number of widely publicized accidents.
Some were less accidental than others.”:
In the controversial arena where Free Radicals meet Nerve Gas, the confusion among the Saranarchists and the Sarinihlism movements has sparked a spirited suburban “Rap-on, Wrap-off” exchange. Saran being relatively benign in a wrapping-exchange, is often mistaken as Sarin-based escalation, leading to occasional less-benign unwrappings of the Sarin variety.
In the battle for Better taste and freedom from Oxygen-oppression, these clashes of nomenclature confusion has garnered negative attention, more so than any West Side Story “stiletto Wrumble.”
In fact, it brings a lot of international bad press.
Along with bringing you further down the short list of "*Parent of the Year*,” it comes with complementary UN Weapons Inspectors and supervision by the Division of Family Services. Both of which have revoked my sandwich license. My appeal to the Sarinity Commission is about to wrap up.
Keeping my Salad Tossed and Tabun-toes crossed. ;-)
Sincerely,
Deandra
HTTPS://www.Twitter.com/DuchessVonD
HTTPS://DuchessVonD.substack.com
u/jtjdp
AskChemistry
​
​
​
If they were holding ***Thebacon*** for you, and your phone was the focus of a serious law enforcement investigation, i.e. it was being wiretapped, this could lead investigators to a wide ranging conspiracy involving late night visits by a pizza delivery driver known as “Big Papa John,” a consigliere known as Suge “(Diet) Tootsie Pop” Knight, who would finger you as the leading Don of thebacon empire: “*El Chapo of the Pizza Toppings*”
If you’re more gung-ho about your pork derivatives and aren’t easily dissuaded by a 1%er Outlaw Meat Lovers-Motorcycle Lifestyle, then perhaps you will risk your freedom fuckin’ around w/ felonious Pork Fritters.
Beware of wide-ranging federal indictments for “*Conspiracy to Distribute Controlled Pork Derivatives*.”
I’m not pulling anyone’s leg, or pulling any pig’s tail, or leading around a swine by the nose-ring, this is a seriously overlooked arena of Pharmaco-Porcine Jurisprudence.
It could even lead to a proliferation of the underground opioid market. In this same manner, fenta-fried El Chapos could later abuse the legal tennant of “Pork Privilege” by simply converting to Islam or Judiaism and claiming KosheHallalkhic privilege: *If thebacon doesn’t fit into dietary law, then how can it be used to settle drug dealing law?*
The delivery of ***controlled bacon*** is not viewed as a laughing matter. And, if the bacon is serious enough, it can result in prison time.
If you are ever again faced w/ a “Meat Lover’s Trio” paradox, such as being forced to choose between the tenants of pepperoni, sausage and bacon, here's an idea: Please hold the pepperoni, before messing w/ thebacon.
If thebacon fits, you don’t acquit.
Don’t do the swine, if you can’t do the time.
I like it when you call me Big Papa…John’s. Put yo' ham in the air, if you a bacon-playa.
Is it Dilaudid or Digornio’s?
--------------------------------------------------------------------------------

Saran Wrap v. Sarin Wrap: Saranocialism vs. Sarinihilism

The frequent single-letter confusion of the plastic PVDC sandwich wrap (Saran) with the nerve gas (Sarin) is a tragedy that brand name marketers on the sandwich wrap side of the Nash equilibrium could have done a better job of anticipating. The world need not go M.A.D. at the drop of a vowel. The ensuing polymer-based political crises and the spillover into the wider arena of Saranocialists vs Sarinihlists during the Sirhan-Saran Conflict. This has left an enduring and highly oxidized legacy across the Pan American Rust Belt.

The Rise and Fall of Polyethylry

Saran Wrap was invented in 1933 by Ralph Wiley. The nomenclature upon which the brand adopted its nome de franca fell upon Wiley’s boss, who chose to name the wrap after his Wife and Daughter. Sarah + Anne = Sarahanne = Saran. (that's a wrap)
The original Saran formula used a polymer of [polyvinylidene chloride](https://en.wikipedia.org/wiki/Polyvinylidene_chloride) (PVDC), which was renowned for its impressive oxygen impermeability, self-adhesion, and all around Stickiness. The protective anti-oxygen-membrane was immensely useful to the preservation of meats from spoilage; its use to preserve both Canadian bacon and breakfast ***bacon*** made the film legendary and essential among the industry shotcallers.
In a controversial 2004 decision led by leading vegan authorities and the (free)-radical political-arm of the “National Saran Devinylization of PVDC” (acronym: “NSDAP”) the more politically expedient successor to the “Saturated Fat Commission,” PVDC was dropped by the Manufacturer in favor of low density polyethylene.
This preserved some of the properties, but sacrificed the legendary oxygen impermeability. Oxygen permeability increased nearly 3333-fold. From 0.6 in the original PVDC based polymer to 2000 cm3 μm m−2 d−1 kPa−1 permeability of the polyethylene based replacement.
Saran Wrapped sandwiches are a frequent paraphernalia associated with soccer moms.
According to “Helicopter Parent Press” the 2004 disenfranchisement of Saran Wrap oxygen-integrity has resulted in a move towards the Bacon, Lettuce, Mayo (BLM)-alternative known as the Sandwich Baggie. The oxygen permeability of these bags is lower than the Saran polyethel-switch. Leaving lettuce to wilt at the hands of radical oxidation.
This sparked widespread controversy in “consumer-brand based political circles.”
A cult of “wrapid (free)-radical opposition to the polyethylamorous wrap” has emerged as a growing outspoken minority.
Personally, I am sentimental for the Latter-Day Saran-Saints. Obviously, I could do without sister wife competition, and the increased premiums paid for “Polygamous Life Insurance.”
Otherwise their position seems to be based on sound politico-polymeric permeability. While the Polymer Proletariat may disagree, I am of the conviction that “Not all polymers are made equal.” Some serve a higher purpose than others. Some take out the garbage, others bravely defend our sandwiches against Romaine lettuce social-spoilage. Different roles for different petropolyamorers.
While PVDC was removed from the Saran-family long before I became the Petrochemical Industry’s “Shadow Commissioner on Tasteful Branding,” I’m a big proponent of reused bacon and less-excited about the proliferation of aerobic bacteria on my soon to be consumed, rewrapped deli meats.
The removal of Saran-based prophylaxis has resulted in the disenfranchisement of millions of soccer moms (whose ranks I’d gladly join if I could find a worthy stud farmer).
The 2004 election of Low-Density Polyethylene over the conventional PVDC has resulted in a schism of the Soccer Mom Caucus. Many radical party members have accused the industry of oxygen-barrier fraud.
An industry-backed propaganda campaign aimed at the hearts & minds of the outspoken opposition was themed “What’s safe for the pan, is safe for Saran.”
The (free)-Radical members of the Helicopter Parent Coalition adopted a counter-campaign entitled “Make Saran Safe Again.”
The more militant “Dads Against Polyethylry”movement changed their name to the the epic “*Saran Sirhan*.”
(Labeled by the Kenned family-owned Low-Density Polyethylene industry as the “SS”)
Sarin Wrap, a nerve agent, that finds few friends, esp in hotspots such as Northern Iraq and Tokyo Subways (where the sandwich meets the tracks) isn't as welcome in the environs of the suburban SUV as, lets say, PB&J, Cheez-Its and Frito-Lay. It’s nomenclature confusion with the pro-Saran movement has resulted in a number of widely publicized accidents.
Some were less accidental than others.”:
In the controversial arena where Free Radicals meet Nerve Gas, the confusion among the Saranarchists and the Sarinihlism movements has sparked a spirited suburban “Rap-on, Wrap-off” exchange. Saran being relatively benign in a wrapping-exchange, is often mistaken as Sarin-based escalation, leading to occasional less-benign unwrappings of the Sarin variety.
In the battle for Better taste and freedom from Oxygen-oppression, these clashes of nomenclature confusion has garnered negative attention, more so than any West Side Story “stiletto Wrumble.”
In fact, it brings a lot of international bad press.
Along with bringing you further down the short list of "*Parent of the Year*,” it comes with complementary UN Weapons Inspectors and supervision by the Division of Family Services. Both of which have revoked my sandwich license. My appeal to the Sarinity Commission is about to wrap up.
Keeping my Salad Tossed and Tabun-toes crossed. ;-)
Sincerely,
Deandra
HTTPS://www.Twitter.com/DuchessVonD
HTTPS://DuchessVonD.substack.com
u/jtjdp
AskChemistry

Morphinan History X - A Survey of Opioid Stereochemistry - Part III: Further Ring Fusions

REVIEW:
Part I of this monograph on opioid stereochemistry-ligand geometry established some foundational concepts such as stereospecific binding (SSB) [Goldstein, PNAS, 1971, v 68, p 1742], that is, the preferential affinity of one stereoisomer over another at bio receptors. Also explored were the steric effects of the most influential shared structural feature of the morphinan nucleus: cis-(1,3-diaxial) fusion of the imino-ethano system in the D-ring (Piperidine).
As a result of the nature of the constrained morphinan nucleus, this iminoethane bridge, anchored at C9 and C13, is forced to one side of the molecule. This provides steric hindrance which blocks access to the important C-ring of morphine derivs such as thebaine, forcing Diels-Alder cycloaddition to form the 6,14-endo adducts upon the reverse face of the C-ring.
Part I related how these steric limitations force dienophiles (during Diels-Alder rxn) to attack the diene system of thebaine from the least sterically hindered side of the morphinan nucleus (http://ineosopen.org/io2106r).
The electron-rich C-ring of thebaine allows for the ready cycloaddition of a diverse range of dienophiles leading to a range of Diels-Alder adducts [Tetrahedron, 1973, 29, 2387]. This includes unhindered dienophiles [KW Bentley, “The Alkaloids” (1971) v 13, p 75], substituted ethylenes [Tetrahedron, 1979, 30, 1201], nitroso carbonyls [JCS Perkin Trans I, 1981, p 3250] and nitroso arenes [JCS Perkin Trans I, 1979, p 3064].
The cycloaddition occurs under electronic control with C7-substitution occurring exclusively with very little, if any, isomeric C8-substituted product. Most of the adducts have 7-α stereochemistry. The notable exception to this being acrylonitrile dienophiles which favor 7-β formation [JACS, 1967, 89, 3267].
The most important takeaway from this molecular C-ring song-and-dance routine is the formation of the 6,14-endoetheno bridge in a critical endo orientation on the reverse face of the morphinan nucleus, allowing for an important hydrogen bond interaction between the 19-OH and 6-OCH3. While the 6-oxygen function is nonessential to high MOR affinity in the pentacyclic morphine series (cf. desomorphine has 10-fold morphine potency despite a complete lack of 6-substitution), this critical 19-OH/6-oxygen hydrogen bond brings the 6-oxy back to the limelight as this H-bond imparts the bridged oripavines with enhanced mu-affinity, allowing for key binding site interactions between the ligand and amino-acid residues of the binding pocket. SAR reviews of bridged oripavines:
Ann Rev Pharmacol 1971, v 11, p 241
https://doi.org/10.1038/nature10954
Part III moves outside of the D-ring and investigates morphinan ring fusions elsewhere in the nucleus. Stereochemistry in the higher level morphinan series can related to simpler tricyclic ligands, such as the 6,7-benzomorphans. Steric and conformational effects in the morphinan nucleus will be related to bioactivity. Later chapters in this series will expound upon the stereochemical-activity relationships in the morphinan series and touch on the broader steric factors in the medicinal chemistry of opioid ligands.
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Progression of Opioid simplicity according to decreasing complexity
Adapted from https://sci-hub.se/10.1002/0471266949.bmc251 and https://sci-hub.se/10.1213/00000539-198402000-00010
​

One in the B, One in the C: cis/trans-B:C Ring Fusion - Stereoisomerism About C14

Vocab: Epimer - Multi-chiral stereoisomers that vary at a single point of chirality, while leaving the other chiral centers unchanged. Example include the 14(R)-morphinans and the 14(S)-isomorphinans. These epimers vary at the configuration of C14, while the other chiral centers remain the same.

INTRODUCTION:

The unambiguous synth of morphine by Gates [JACS, 1952, 74, 1109, ibid. 1956, 78, 1380; ibid, 1954, 76, 312; Elad, Ginsburg, J Chem Soc, 1954, p. 3052] was a watershed moment in natural product synthesis and provided proof of the Gulland-Robinson postulate, which correctly predicted the structure of morphine 25 yrs prior (J Chem Soc, 1923, p 980, Mem. Proc. Manchester Lit. Phil. Soc, 1925, v 69, p 79).
Gates’ synthesis, however, did not establish the absolute configurations about the five chiral centers of morphine.
The first discussion of stereochem in the morphinan nucleus was that of Schopf (Annalen der Chemie, 1927, v 452, p 211; p 249; ibid., 1939, 537, 143) who suggested that the D-ring (containing piperidine) was oriented trans to the furan E-ring. Schopf's argument, involving a Hoffman degradation product, was influenced by the observations of Fruend et al., innovators in the field of 14-hydroxy substituted derivs of the 6-keto-codeinone [J. Prakt. Chem., 1916, v 94, p 135]. This established the relationship between the 14-OH and the imino-ethano system, but this was not unequivocal evidence that the 14-OH had the same geometry of the 14-H in codeine (and thereby morphine).
Additional evidence for the C14 geometry was provided by LF Small (J Org Chem, 1939, 4, 220) and others, but the ambiguity of the all important C14 remained for quite some time [JACS 1952, v 74, p 2630; JACS, 1953, v 75, p 5329]. The elucidation of C14 stereochemistry would not fully emerge until more definitive evidence emerged [Barton et al. provides good summaries in Proc. Chem. Soc., 1963, p. 203]
The full elucidation of morphine stereochemistry [JACS, 1956, 78, 4619] and absolute config [Helv Chim Acta 1955, 38, 1847] allowed for later authors to perform unambiguous degradation studies that extended a number of helpful stereo-relationships to other morphinans, such as levorphanol [Helv Chim Acta, 1959, 42, 212] . The 5H, 6H, 14H are all oriented cis to the imino-ethano system (in the same plane) which, as we learned in “Part I,” is cis-fused to C9 and C13.
https://i.imgur.com/5d9bOBv.jpg
Shows the relationship among the C14 variants of the morphinan nucleus.
There are eight diastereomeric pairs, 16 stereoisomers, in the pentacyclic morphine series. Natural l-(-)-morphine is configured 14(R) at C14. The most significant variants thus far explored in the literature are those that vary at this carbon. It's 14(S)-epimer, isomorphine, features an inverted configuration about C14. This has consequences for bioactivity.
As we have seen with D-ring and imino-ethano cis-(1,3-diaxial) fusion, the constraints imposed by ring-fusion in the morphinan system influence the chemistry and conformational flexibility of the entire hetereocycle. We will now explore another important ring fusion and the effects this has on bioactivity…
B:C Ring Fusion: 14(R)-Morphinans vs 14(S)-Isomorphinans
All 4,5,6-ring morphinans (and juxtaposed trans-B:C isomorphinans) feature a D-ring iminoethano system locked in a cis-(1,3-diaxial) orientation. All of this ring fusion has stereochemical consequences.
Lacking the C5/C6 substitution of pentacyclic morphine, tetracyclic morphinans (levorphanol) have three centers of asymmetry: C9, C13, C14.
By the theoretical formula 2^n, levorphanol should have 2^3 = 8 possible stereoisomers. Thanks to the restricted rotation about the alicyclic junctions, the actual number of possible stereoisomers is reduced by half, making only two diastereomeric (racemic) forms possible.
These can only differ at the junction of rings B:C (C13-C14). Since C13, the all-carbon center, is locked down tighter than a “Fentafort Knox”, these cis-trans diastereomers can be thought of as differing in the configuration about C14.
In plain vanilla (cis) morphinans, including morphine, thebaine derivs, levorphanol and DXM, the B:C rings are cis-fused while the C:D pair are trans. Hence, cis-B:C and trans-C:D ring fusion.
Not surprisingly, we call the isomeric morphinans with the opposing trans-B:C ring fusion, ISOMOPRHINANS. The fusions here are trans- between rings B/C and cis- between rings C/D.
The technical terms for these relationships are trans-decalin fusion (B/C ring fusion) and cis-decahydroisoquinoline fusion (C/D ring fusion). The difference being the amine function in the D-ring piperidine causes the decalin structure to become an fully saturated isoquinoline ring structure.
​
​
An Edge-on B-ring view of trans-B:C fused ISOMORPHINAN w/ alt views inset (upper left and upper right).
Cis-B:C fused morphinans have (R)-configuration at C14. While the trans-B:C fused series, isomorphinans, have 14(S)-configuration.
Another term for isomorphinan is 14(S)-morphinan. The absolute configuration varies at C14.
In the cis-morphinans/morphine, the bonds connecting the B-ring to the C-ring are oriented in the same geometric plane. That is, the carbon-carbon bonds at C14-C8 and C13-C5 are fused in the same geometric plane.
These same C14-C8 and C13-C5 bonds in the trans-B:C fused series (including isomorphine, isocodeine, isothebaine, and isolevorphanol) are fused trans, in opposite geometric planes.
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​
Morphinan/Isomorphinan at top. The C14-C8 and C13-C5 bonds of morphinans are in the same (cis) geometric plane (dotted lines oriented away from viewer). The C13 all-carbon center remains locked in place in both isomeric morphinans, while the C14-C8 bond in isomorphinan is opposed (trans). The single point stereo-mutation is at C14.
​
B/c this iminoethano cis-(1,3-diaxial) fusion remains constant in every morphinan and isomorphinan isomer, the relationship between the B:C and C:D rings will be opposite of one another. If the B:C rings are fused cis, the C:D rings will be fused trans. And vice-versa.
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https://preview.redd.it/oief01fkzsy91.png?width=2048&format=png&auto=webp&s=e99c8f972ace3053f4db3b43e133b7bae738c121
Another way to classify morphinans/isomorphinans is by the relationship between the hydrogens (or other substituents in the case of the 14-hydroxy derivs) at C9 and C14.
9H and 14H are oriented trans, or opposite geometric planes, in the 14(R)-morphinans. The 9H-14H pair in the 14(S)-isomorphinans are cis, or the same geometric plane. Isomorphinans are sometimes distinguished from morphinans by simply reversing the orientation of the 14-H (from R to S), indicating to the reader that the morphinan being referenced is that of 14(S)-isomorphinan.
The (14S)-morphinans w/ a saturated C-ring form a B:C ring system that we call cis-decalin. The 7,8-dbl bond of morphine/codeine removes two hydrogens from the B:C decalin system, forming a cis-octalin. The C:D ring in morphine is a trans-octahydroisoquinoline (trans-OHIQ)
​
cis/trans-decalin - the B:C rings form a cis-decalin system in morphinans and a trans-decalin in isomorphinan; while the C:D rings are trans-decalin in morphinans and cis-decalin in isomorphinans
https://i.imgur.com/d1WYtpo.gif [alt view of cis/trans-decalin systems]
As a result of the system’s rigidity, a cis-morphinan with a cis-decalin system in rings B:C will have the opposite relationship between the C:D rings, trans-decalin. This C:D relationship is technically a trans-decahydroisoquinoline. This has essentially the same general geometries as the trans-decalin system (as seen above), with the substitution of a nitrogen for one of the carbons in the decalin system.
In keeping with the opposite nature of the trans-isomorphinans, their C:D relationship is oriented cis-decahydroisoquinoline.
​
Alt View of the 14(R)-morphinan (right) 14(S)-isomorphinan (left)
KW Bentley - “The Chemistry of the Morphine Alkaloids” (1954), Oxf. Univ Press
D Ginsberg “The Opium Alkaloids” (1962) Wiley
Another way to distinguish iso- from the regular morphinans is the orientation of 14-H. The 14-H is axial in the morphinans. The 14-H is equatorial in the isomorphinans.
https://i.imgur.com/UaFniwP.png
[The cis-decalin “ring flip” are two different orientations of the same system, both are equivalent (left image); the axial and equatorial orientations of substituents relative to a cyclohexane ring (right image)]
The axial position means the hydrogen (or another substituent) is positioned in a perpendicular geometric plane to the rest of the ring system. The equatorial substituent projects into a Geometric plane that is parallel to that of the edge of the ring. If a viewer is facing the cyclohexane system edge-on, the equatorial substituent will be pointing out directly toward the viewer. An axial substituent will appear at a 90 deg angle in most chemical diagrams, appearing to be mounted either above or below the plane of the ring system.
The influence of axial-equatorial substituents can have variable effects on the bioactivity of stereoisomers. We can see this variable effect in derivs of anazocine (P-7521). P-7521, which is the designation for the N-phenethyl and 9-meta-phenol deriv of anazocine, the effect is minimal, or, at least, the receptor preference for an axial-equatorial 4-phenyl group does not stay consistent in the unsubstituted phenyl and the meta-phenolic analogues: https://i.imgur.com/GeG9T2v.jpg
[REFS for this section are included in the comments]
The orientation of the 3-methyl group is of greater consequence in the alpha-/beta-prodine series. Here the effects are more dramatic. The axial-methyl in alphaprodine depresses activity relative to the beta-epimer. The equatorial-methyl of betaprodine enhances activity 10-fold.
​
axial vs equatorial 3-methyl isomers and their effect on potency
https://sci-hub.se/10.1111/j.2042-7158.1955.tb12115.x
An even more dramatic example of the impact of axial-equatorial substitution on activity is in the stereoisomers of 3-methylfentanyl (3MF).
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diagram of 3D configurations of the C3 and C4 stereocenters in the four 3MF stereoisomers
​
Insertion of the 3-methyl transforms the achiral fentanyl into a diverse chiral zoo with two stereocenters, at carbons C3 and C4 on the piperidine ring. Two diastereomeric pairs (cis/trans), each with two enantiomers (dextro/levo). Giving 3-methylfentanyl a total of four stereoisomers.
The (3R,4S)-cis-(+)-3MF isomer (R 26800), where the 3-Me is oriented axial, is the configuration most preferred by the MOR active site. It has Analgesic activity of 25 x fentanyl and a very high MOR affinity on par with lofentanil and carfentanil.
The opposite (3S,4R)-cis-(-) configuration (R 25830) possesses activity of 0.22 x fentanyl. This features a 3-Me substituent oriented equatorial. The MOR affinity is seven-fold weaker than fentanyl proper. Despite the equatorial methyl being most favorable in the case of beta-prodine, in the case of cis-3MF, the isomer most preferred by the MOR (based on affinity and activity) is that of the 3-Me AXIAL isomer (R 26800)
The eudismic ratio between the cis-3MF distomeeutomer is 90-fold (ED50 values). The ratio based solely on MOR receptor affinity is ~ 20.
It's difficult to find binding affinity for the individual (+)/(-)-antipodes of the trans-isomer, but racemic trans-(d,l) is approx equipotent with plain vanilla fentanyl.
REFS:
https://i.imgur.com/Ot7pguZ.jpg
https://i.imgur.com/2I4HSef.jpg
Leysen et al. “[3H]-Sufentanil, a superior ligand…” - Eur J Pharmacol. 1983 Feb 18;87(2-3):209-25 - https://sci-hub.se/10.1016/0014-2999(83)90331-x90331-x)
“Stereochemical anatomy of morphinomimetics”. In: Neurochemical Mechanisms of Opiates and Endorphins (Adv Biochem Psychopharmacol v 20) p 103 (1979)
https://doi.org/10.1007/978-3-0348-9311-4_3
​

μSICAL CHAIRS? Who Sunk my Bupreship?CHAIR vs BOAT Conformation

In the absence of strong electrostatic effects between functional groups or bond distortions due to unsaturation in the system (cyclohexene due to the 7,8-dbl bond in morphine), the most likely preferred conformation of ligands containing a cyclohexane ring are the chair conformers with a maximal no. of equatorial substitutions.
As we saw with the prodine/3MF example above, this is not a reflection of the axial-equatorial substitution pattern most preferred by the receptor. The bioactive conformer has been a subject of much debate and its found throughout the annals of the Journal of Computational Chemistry. [Casy, Dewar - "The Steric Factor in Medicinal Chemistry" (1993)
The “most stable” means the lowest-energy conformer. That is, the conformation with the lowest overall bond energy in the system.
Boat and Chair conformational isomerism is based on the orientation of the bonds in a cyclohexane (alicyclic) ring or an analogous six member ring, i.e. piperidine. These bonds are in a constant state of flux. The lowest energy conformer will be the one that the ring system assumes most of the time. Unless constrained by unusual C-ring contorted geometries, such as in bridged oripavines or a 7,8-double bond (morphine), the C-ring is going to assume a chair conformation. The cyclohexene (morphine, codeine) and the 6,14-bridged oripavines and thebaines have distorted conformations in the C-ring. These have boat conformations.
Morphine and codeine are referred to as a half-boat. Their cyclohexene C-ring is twisted up wreck like the battleship Bismarck (i.e. “Sunk Boat”). Using naval terminology, the technical term for the alpha-6-OH (or 6-OCH3) is bowsprit.
https://i.imgur.com/UeGnCZf.jpg
Morphine with a C-ring bowsprit half-boat conformation.
This orientation is less preferred by the MOR, resulting in lower activity compared to that of the fully saturated C-ring derivs such as desomorphine and the 6-keto series (hydromorphone, oxymorphone).
https://i.imgur.com/gOj5wxe.jpg
N-phenethyl-nordesomorphine (above) with nearly 80-fold the potency of morphine demonstrates the lack of importance of the 6-OH.
This boat orientation has key advantages, however, in the bridged oripavines. It allows for the “russian nesting doll situation” (cf. Part I) in which the 19-OH can form a H-bond w/ the 6-oxygen function, wrapping up the C-ring like said babushka doll and delivering it to the lusty mouth of the receptor with a cute little bow.
Thebaine itself is a feeble analgesic (toxic and pro-convulsive on its own). The lack of inherent activity is due to the diene system, which causes the C-ring, and most of the molecule, to appear planar (as in Flat as a Pancake). We reviewed the consequences of this planarity for Lil Thebby in the Diels-Aldedienophile section of Part I.
​
Short Bus Boat = the \"Rain Man\" (Dustin Hoffmann) of boat coformers; when its not counting toothpicks on the floor, it wears a helmet for its own protection
The shape of the boat conformer looks like a banana boat. As in the shape of the aluminum Reynolds Wrap smokagami that my old Oxy dealer taught me to make back in an era when a 100-ct bottle of OC80s sold for $350.
And “pressies” were what Elmer Fudd enjoyed eating in the “Brweadroom.”
This was another era (nearly 20 years ago) where opioids were more innocent and didn't have the same fentalogue-based sentiment attached to their use.
“Pressie” was also how this very awkward teenager with a mouth full of braces described the well-dressed kids who made fun of her at school. [cf. “Pressie Plastards!” / “Wascally Wabbits!”]
To use a naval analogy, pressies were the British Naval press gangs that forced sailors into their ranks and one of the causes of the War of 1812. (A lot can change in 15-years!)
How OC80 tabbys become fetty-pressies is a linguistics nightmare and my degree in differential slanguistics has been collecting dust for about as many years as has the last remaining legit OC80 has been collecting dust in some obscure pharma museum at ObscureDrugs
Those cute ersatz foils upon which you smoke your pressies may be a cute mnemonic device, but it provides much to be desired in regards to optimal bioavailability of acid-addition amine salts (HCl salts). [clue: most of your product is going up in smoke, literally]
Vaping HCl salts from a banana boat (trans-foilia) is akin to dressing up your bananas in pyjamas before making banana bread. You wouldn’t dress an OC80 into a onesie made for a bambino. Why would you sacrifice 90% of your “bioavailabido” to a Burning Bush? For us who are slammies in pyjamies, such tom-foilery is anathema. (SEE COMMENTS)
​

In the fully hydrogenated morphinans, levorphanol and oxymorphone, the C-ring is oriented in chair conformation. This alicyclic ring looks like the hipster’s most indispensable piece of overpriced lawn furniture: the Adirondack Chair. Hence the name.

Just like a hipster paying top-dollar for free-range, organic splinters, the chair conformation takes home the 4H blue ribbon. The chair is a relaxing, gentile “sipping sherry on the veranda” occupation. Low energy, lethargic, perhaps a bit of a belly from one too many India Pale Ale-Kombucha Jell-O shots (Kombucha is essentially just overpriced Boone’s Farm for those w/ excessive disposable income; a “Hipster Winecooler”).
If the cyclohexyl world is the Ronald McDonald universe, the chair conformer is the molecular Grimace of the BK Bounce House. Make fun of the slow, bumbling glob of partially hydrogenated vegetable oil all you want. At the end of the day, the chair goes home with the MOR.
In other words: the chair is energetically more favorable than the boat. That is, the chair is lower energy than the boat conformer.
​
brief list comparing the C-ring conformations of misc morphinans, courtesy of G. Lenz et al. “Opiates” (1986) - see Chap 4 of said monograph for a list of studies
As such, tetracyclic (levorphanol etc) and pentacyclic (oxymorphone etc) morphinans with a C-ring in chair conformation are the conformers with the highest mu-opioid receptor affinity (highest bioactivity). In the tetra/pentacyclic morphinan series, the boat will usually have lower affinity at the MOR, translating to lower bioactivity.
Numerous studies have been carried out to predict the likely conformation of the bioactive species. Lower energy receptor-ligand complexes are the most stable. As such, the lower energy chair conformation will be the more likely bioactive conformer. The boat is higher energy and therefore is only assumed if necessary due to the nature of bond-related hijinks. (cf. 7,8-double bond in morphine)
Below is a decent mnemonic device to help keep track of the lowest energy cyclohexane conformations:
You burn very few calories relaxing in your chair. (low-energy)
Boats, however, are nasty oil-burning, smoke belching behemoths. (higher energy) Boats do occasionally have greenhouse emission-competition on the high seas, but this only occurs when whales swallow Pinnochio and Gepetto. [Walt Disney et al.; this topic is explored in greater details in my Reddit satire collection]

Stereochemical-Activity Relationships, Part I: The Junction of Geometry and Function

Stereostructure-activity relationships (SARs) in the morphinans...
With a good deal of synthetic effort, the typical cis-decalin orientation at the B:C ring junction can be inverted to yield the opposite orientation in the morphine molecule. This converts the natural 14(R) to the opposite 14(S) configuration isomers: trans-codeine and trans-morphine. These are disappointing analgesics with activities that are 0.5 x codeine and 0.1 x morphine, respectively. (J Med Chem, 1970, v 13, p 973; Chem Pharm Bull, 1973, v 21, p 2004)
Grewe cyclization can be modified to produce isomorphinans in relatively high yield. (Adv. Biochem. Pharmacol., 1974, v. 8, p. 51) The original synthesis of isomorphinans was an outgrowth of the Gates morphine route (J Med Chem, 1964, v 7, p 127).
Gates found that isolevorphanol (the trans-B:C fused levorphanol isomer) is 10 x the potency of morphine, approx twice as potent as the plain vanilla levorphanol (JACS, 1958, v 21, p 2004).
The 14(S)/14(R) ratio in l-isomorphine/l-morphine is 0.1. The same ratio in the 14(S)-isolevorphanol/14(R)-isolevorphanol series is TWENTY fold higher, that is 2.0. What gives?
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https://preview.redd.it/2gj0t2li1ty91.png?width=369&format=png&auto=webp&s=d2168e338a8d2833abcd43c7d7094e55ec893e20
The awkward half-boat C-ring in isomorphine (fig I) is clearly more distorted than the orderly chair conformation assumed by the trans-B:C tetracyclic isomorphinan system (fig II; isolevorphanol has an added 3-OH substituent which does not affect stereochem).
The anomalous 14(S)/14(R)-isomer pharmacology differences between the isolevorphanol (2 x potency of cis-B:C levorphanol) and isomorphine (0. 1 x potency of cis-B:C morphine) has a lot to do with the C-ring distortion caused by the 7,8-ene. Other factors, such as the presence of the fifth E-ring (furan ring) in the pentacyclic isomorphine and the 6-substitution, both of which are lacking in the tetracyclic isolevorphanol, likely play an important role as well.
​
​
trans-B:C isomorphine featuring the distorted half-boat conformer in which the 6-OH has been significantly juxtaposed compared to regular morphine]
The furan (E) ring in 14(R)-isomorphine is somewhat contorted relative to its orientation in the cis-B:C 14(S)-morphine. The C5 (alicyclic) side of the 4,5-ether bridge is forced to assume a slightly different angle than that of the C5 bridge in morphine (fig 35). This, combined with the 7,8-double bond system forces the C-ring of isomorphine to form a "folded-up" half-boat, in which the C-ring folds-in on itself from the opposite side of the C-ring (relative to the half-boat conformer in (14R)-morphine).
This does not change the orientation of the 6-H/OH relative to each other (the 6-OH is still oriented in the alpha position relative to the 6-H), but it does manage to change the orientation of the 6-OH group relative to the 6-OH configuration seen in 14(R)-morphine. This 6-OH group, while less important than the critical meta-phenol, does form an H-bond interaction with amino acid residues in the MOR ligand binding pocket (the MOR active site). Distortions to this group will affect these interactions and, in the case of isomorphine, lead to lower affinity.
While the B:C trans-decalin orientation in isolevorphanol (lacking a 6-OH is clearly advantages in regards to bioactivity), the trans-octalin B:C configuration in isomorphine causes the 6-OH to assume a disadvantages geometry that interferes with important AA residue interactions at the MOR active site.
The 14-H oriented equatorial, which has advantages in isolevorphanol, matters little to isomorphine, as the C-ring is greatly distorted due to C14 inversion to the 14(S)-configuration.
Tetrahedron, 1969, 25, 1851 184
JACS, 1962, 84, 4125
KW Bentley, “The Alkaloids, Vol. XIII” (1970)

HISTORICAL DETERMINATION OF ABSOLUTE CONFIG

Determining the absolute configuration of chiral compounds has presented a challenge in earlier eras. Today, we have a variety of fancy-pants techniques to investigate chirality and to help assign absolute config. These techniques include X-ray crystallography (most common, albeit w/ some limitations), optical rotatory dispersion (ORD), vibrational circular dichroism (VCD) [https://sci-hub.se/10.1007/128_2010_86; https://www.mdpi.com/1420-3049/23/9/2404], UV-Vis, and [1H]-NMR.
Many surveys on opioid and morphinan abs-config have been compiled for use by more advanced readers. [AF Casy, G Dewar - “The Steric Factor in Medicinal Chemistry” (1993)]
One of the most comprehensive crystallographic monographs is by Tollenaere et al. (Janssen Pharma colleagues) “Atlas of the Three-Dimensional Structure of Drugs” (1979, Elsevier). This covers psychoactive drugs from a broad range of classes. Janssen has a storied history of narcotic innovation and includes a number of opioid structures. As the Atlas is not avail in ebook form, some of these are included in this survey.
More opioid geometries are found here:
https://imgur.com/gallery/MVNJHO5
Earlier eras, in which, adv instrumentation was less readily avail, were able to establish stereochem by unambiguous synthesis and degradation studies. The absolute configuration of a known molecules was then related the configuration about these established chiral centers to similar compounds by a technique called foot-printing.
AH Beckett used chiral foot-printing to gather some of the first evidence supporting the shared configurations of the more active eutomers of the morphinans and benzomorphans.
http://sci-hub.se/10.1111/j.2042-7158.1960.tb10480.x
http://sci-hub.se/10.1038/1791074a0
“Foot-printing” uses silica-gel impregnated with a compound of established stereochemistry, such as levo-(-)-morphine (they’re going to name the baby “Lil’ Thebby” if it's a girl, and “Coddy” if it’s a boy).
Beckett then compared how well the impregnated silica adsorbed the more active eutomers (levorphanol, levo-(-)-phenazocine, etc) and compared this with adsorption of the less-active distomers (dextrorphan, d-(+)-benzomorphans, etc). This is known as stereoselective adsorption.
Obviously, the use of “chiral impregnation” was less popular back then as it was not something that polite society thought Humphrey Bogart would say onscreen.
When the OBGYN, looking like a stirrup-wielding dwarf armed with a headlamp and speculum, is staring up my "cunniltography column", the last thing I want to hear the doctor say is: “Here’s looking at your*, kid*.”
That’s not B:C-ring fusion, but a case of “Birth Control failure.”
Beckett et al. found that levorphanol was adsorbed more strongly to the levo-morphine impregnated-column than that of its dextrorphan antipode. The same was observed in the levo-(-)-5,9-dialkyl-6,7-benzomorphans, which were taken up in greater proportion to that of their dextro-antipodes.
The conclusion Beckett reached, which was later proven correct, was that the active levo eutomers of these classical opioid polycycles shared similar configurations at their key chiral centers with l-morphine.
[Beckett, Angew. Chem. 1960, v 72, p 686; "Stereochemical Factors in Biological Activity" in Prog. Drug Res., 1959, v 1, p 455]
Kalvoda et al. used Hoffman degradation to establish the cis-B:C ring fusion of the morphinans. [discussed in prior section]. The same studies also showed that degradation of thebaine and levorphanol yielded an identical dicarboxylic acid. This dicarboxylic acid had already been related to glyceraldehyde (cf. Fisher’s Genealogical Nomenclature), thereby linking the asymmetry of C13 and C14 of morphine (by way of thebaine) to that of levorphanol. [Helv Chim Acta, 1955, v 38, p 1847; p 1857]
Stork and Rapoport established the absolute configuration at C9 [JACS, 1952, 74, 768; ibid., 1953, 75, 5329; "The Alkaloids", Chemistry and Physiology v 2, p 171 (1952)]. In this way the relationships of the three chiral carbons of levorphanol were unambiguously related to natural l-morphine.
The synthetic tetracyclic morphinans gained a loyal following among Japanese researchers, including the prolific team of Sawa et al. They would publish dozens of studies over several decades exploring the morphinans. Their contributions to morphinan stereochemistry include work on relating simonene, a natural morphinan alkaloid of the opposite config of natural morphine, to dextromethorphan (DXM) [Tetrahedron, 1961, 15, p 144; p 154; Pharm Bull (Tokyo), 1956, v 4, p 237, p 438; ibid., 1960, v 8, p 960]
We’ve seen that variation about C14 in the isomorphinans is a mixed bag. In the morphine/codeine series it can be detrimental to activity. While smaller polycycles like isolevorphanol and trans-fused β-5,9-dimethyl-6,7-benzomorphans demonstrate a substantial INCREASE in potency. Isolevorphanol approx twice as active as the cis-morphinan, while the trans-fused Beta-benzomorphans can be up to 10 x the potency of their cis-fused alpha-isomers.
In fact, trans-fusion in the benzomorphan series takes it to an entirely different level.
Note: When referring to “benzomorphans”, I am referring to 5,9-disubstituted 6,7-benzomorphans. Typically these are 5,9-dimethyl (the type seen in clinically approved benzomorphans, phenazocine, pentazocine, etc) but those with 5-OH/5-alkyl, and other 9-alkyl substituents also have substantial activity.
​
​
https://preview.redd.it/i6o83o383ty91.png?width=1672&format=png&auto=webp&s=e555adc43ee536c712d3b7b81fd13c615032a620
As you have already gathered, the d-(+) enantiomers of the more constrained 6-, 5-, 4-, 3-member polycyclic (classical) opioids are far less active at the MOR. Analgesic activity resides solely in the levo-(-).
The benzomorphan series will introduce us to a rare but noteworthy exception to this eutomedistomer relationship. Some of the dextro-benzomorphans, while weaker analgesics than the levo-antipodes, will be the more euphoric enantiomer.
In some of these ligands, a total of five cases seen in the classical works of NB Eddy & EL May, the majority of euphoria resides in the analgesic-inactive dextro isomer. This is a special case seen rarely in the opiosphere (the only other place I know of this occurring is in certain 4-arylpiperidine derivs), but is more common to the benzomorphans than any other class. It is not known why this occurs. There is evidence that analgesia and dependence-producing phenomena are mediated by different mu-receptor subtypes. A full biochemical understanding of receptor-related conformational phenomena and euphoria and structure-euphoria relationships have yet to be elucidated.
https://i.imgur.com/yPIMM9a.jpg
[IUPAC official numbering (left) vs old-style numbering of the 6,7-benzomorphan system]
The 5,9-disubstituted 6,7-benzomorphans have three chiral centers. These are numbered C1, C5, C9 according to the older EL May/NB Eddy style notation. (IUPAC calls the benzomorphan series benzaocines and uses different numbering, but the historical literature during the time of most benzomorphan SAR studies uses the old style C1, C5, C9 numbering)
​
numbering and abs config in the 6,7-benzomorphan series
​
The stereocenters of benzomorphans correspond to those in the morphinan nucleus as follows: C9, C13, C14 in the morphinans are equivalent to C1, C5, C9 in the benzomorphans (respectively). C13-C14 cis/trans isomerism in the morphinan series becomes C5-C9 cis/trans isomerism in the benzomorphans.
​
https://preview.redd.it/aw4j6ytf3ty91.png?width=2048&format=png&auto=webp&s=f356e727c4d039408117d05153aff2b1724727ad
The analogous relationship between (cis) d,l-racemorphan (fig XLVI) and the (cis) α-d,l-benzomorphan (fig CVI) is displayed in the pair of structures on the left. Note the 14C-13C cis-orientation (same geometric plane) of the B:C ring axis in fig. XLVI (morphinan). This corresponds to the same α-(cis) orientation of both the 5-Me and 9-Me in fig CVI, whose proper name in old-style numbering is (d,l)-α-2’-OH-2,5,9-trimethyl-6,7-benzomorphan (aka: α-metazocine)
The trans orientation of the B:C ring junction in the d,l-isoracemorphan (fig CV - racemic) corresponds to the trans orientation of the 5,9-dimethyl groups in the β-6,7-benzormorphan (fig. CVII) in which the 5-Me and 9-Me which are oriented in opposite planes. The absolute configuration of the carbons of the cis-B:C levo-morphinans (levorphanol, morphine) correspond to the absolute confguration seen in chiral carbons of levo-α 5,9-disubstituted benzomorphans: 1(R), 5(R), 9(S). The levo-β analogues have the same abs configuration of the corresponding chiral centers of isolevorphanol: 1(R), 5(S), 9(S).
While there is less ring fusion in this benzomorphan series, the same cis-trans isomerism exists and it relates to bioactivity similarly to the relationship between cis/trans-B:C fused isomers of the tetracyclic morphinans: the trans-β benzomorphan isomers are up to 15 times more active than their cis-α counterpart.
​
differences between the levo/dextro-cis-alpha and levo-dextro/trans-beta geometries
These 5,9-disubstituted varieties come in two diastereomeric pairs (racemates) that form a total of four stereoisomers: α-cis and β-trans at the C5/C9 junction. Each of these diastereomers can be further divided into the individual optical isomers: dextro-(+)- and levo-(-). Making a total of four stereoisomers.
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α-cis, β-trans 5,9-dimethyl 6,7-benzomorphans
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https://preview.redd.it/425736mm3ty91.png?width=1675&format=png&auto=webp&s=f75419ea78c9a31b47cfc637fbf77e5186f3ae23

Morphine is considered to the the Proteus of Organic Molecules.

As the first alkaloid isolated from plant matter and done so on an industrial scale, it became the Proteus of the modern pharmaceutical industry and inspired the field of natural product chemistry. The first major SAR elucidation efforts were conducted by the American NRC team of LF Small, NB Eddy and EL May beginning in 1929 in order to find morphine derivatives that had reduced addiction liability. Thus, morphine, or the search for safer mu-opioid receptor agonist analgesics, is the forefather of the field of Medicinal Chemistry and modern SAR Elucidation is based upon techniques developed during these early SAR invesgitations. --------------------------------------------------------
In one of the many ironic twists of history, white European Cartels of the 19th century forced Chinese merchants to continue purchasing their opium. When the Chinese passed some of the first drug control laws, the economic importance of Indian Opium sales to China necessitated gunboat diplomacy and sparked a brief series of wars.
After America had their own devastating Napoleonic-era conflict, the generation that fought that war, inherited a condition of morphinomimetic habituation to a degree and scale not observed since. Known as the "Soldier's Disease" it affected many Civil War veterans throughout their entire lives. The opioid crises of today is nothing new. History is cyclical and there is always something to be learned through well versed retrospectives.
I've spent 15 years of my life working as a medicinal chemist in the arena of opioid development. I've worked with all the subtypes: mu, delta, kappa, and NOP/ORL1. I've studied them on three continents and worked with them under a variety of regulatory regimes.
Unlike most professionals in the healthcare field, I'm not afraid to discuss my own personal struggles with opioid addiction, which I certainly took to "another level" and developed some monster tolerances to some novel and highly potent agonists. While I don't consider addiction to be a moral or criminal issue, it rarely improves the lives of those trapped it in its cycles. It's a disease state just like any other and, unfortunately, the responsibility for this generation's "crises" rests at the feet of my own industry.
The literature survey I present here are filled w/ sarcasm, lighthearted humor and a few personal anecdotes. There's plenty of meat and potatoes to be had. But through anthropomorphizing these quantized molecules, perhaps I can make the topic of classical morphinan SAR more fun, flippant and digestible.
Enjoy. --Deandra aka: Duchess Von D
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Molecusexuality of Opioid Stereochemistry: The Morphinan In the Mirror, Part IA: non-IUPAC approved Molerotic adventure in anthropomorphic Molecular sterics

By:
Edie Norton w/ a Fire Crotch, Sufentstress of the morphinomimetic mattress, the π-pair-o-skinny-jeans molecuho, Mini-Thinny Mouse, the RemiFenny Skank, the μ-gμrμ…
Dμchess Vσn δ
A well cited exploration into the Stereochemistry, Geometry and Sterics of the Opiosphere
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The idea for this post came about as I was working on another post about N-aralkyl substituted morphinans entitled “Tetracycles in Tiaras”. [see u/jtjdp for this post]
In prep’n for that post, I did my typical image hosting on Imgur. The concepts of cis-(1,3-diaxial) piperidine fusion, cis-B:C and trans-C:D ring fusion are important to the morphinan and polycyclic classes. As such, several of my images featured these cis/trans (molecular) orientations quite prominently. It soon earned a slew of downvotes.
I discovered the reason for this lack of opio-enthusiasm when a confused Imgurian left an interesting comment:

“Yo, why do you gotta assign genders? Can't they just make up their own minds and live their own lives w/o you forcing your own binary genders?”

For chemists out there, this certainly was hilarious, but i decided to humor this Imgurian and imagine a world where his polarimetry correct views applied to quantized matter like any other civil or fundmaental human right.
Technically these molecusexual orientations were assigned by people. While they aren’t genders as much as geometric orientations, either way, it is forcing nomenclature onto a quantized state of matter. And forced conformations are no a laughing matter.
Forcing a Fetty to be a Frannie, or a Diladdy to be a Maddy, or a Thebby to be Thaddy, is in contravention to the “UN Resolution on Stereochemical Self-Determination.”
A clear cut “heroin rights violation.”
------I'm going to pause for a moment, and allow that rapid fire burst of punnery to fully set in------
But enantiomers don’t resolve themselves. They need a helping hand.
And that’s how I came up with the idea for Molecusexuality.
Clearly there is a need to explain the long history of the brave pioneering molecules that came out of the cis/trans closet long before the LGBTQ community was even a thing. Nature lead the charge. Humanity eventually followed.
There are some reactions, such as the Knoevenagel (benzaldehyde + nitroalkane + n-butylamine), which still remain in the closet, at least until the resulting nitrostyrene provides the confidence needed to stand proud outside of said closet.
The DEA has been engaging in molecular eugenics for fifty years. They split hairs on matters of cis/trans 4-methylaminorex, dextro-/levo-methorphan and countless other higgedy-piggedly matters. Forcing molecules to conform to arbitrary legal codes is as absurd as the concept of prohibition.
Statistically speaking, molecules are braver than man. This, of course, was left out by the mainstream press during Pride Month. I’m here to set the record 109.5 degrees/Tetrahedral.
I’m a medicinal chemist, self-experimentalist in the same vain as Hoffmann and Shulgin, but when it comes to morphinans and 5,9-dialkyl-6,7-benzomorphans, I’m all about the absolute configuration of C(14).
In fact, even among the 14(R)-cis-morphinans, i.e. Morphine, cis/trans isomerism is always in play within the the same molecule. The B:C rings exist in a cis-decalin fusion while the C:D rings are fused in trans-decahydroisoquinoline arrangement.
The quantum duality of cis-trans ligand-bendery among the morphinans is Quantum Pride. I’ve made only a few novel discoveries over my career. But I have made many ligands and many of those have graced my spoon.
Of the ~ 25 of these that are of the Opioid variety (especially near and dear to my blood-brain barrier), many have been chiral. As such, they involve a range of stereochemical relationships that are important to their chemical reactivity and bioactivity.
That’s only counting successes. Many were failures. And many of those were due to incorrect stereochemistry. I will share examples with you during the intermissions, entitled: “Epic Failures in Stereoisomerism.”
In humans, mu-stereotypy tends to suppress libido. Making them less sexy. What about other mammals?
While the lab mice are remaining mum as church mice on these topics, their behavior says all we need to know.
Below is a mouse on morphine.
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“I’m too sexy for this lab, too sexy for this cage, too sexy for rehab…”
More murine centerfolds found here: https://doi.org/10.1111/j.1476-5381.1960.tb00277.x
This is known as a Straub tail. It has been a hallmark of mu-mediated activity since Straub first noted the phenomena in 1911. They call this a "narcotic cue." And it is still used today as indicative of mu-mediated stereotypy.
I'm here to make opioids and the average SAR narrative into a soap operatic adventure. Perhaps not as sexy as John Stamos on General Hospital, but with a little help from my brand of prose, help guide you into ligand lust. Welcome to the world of Molecu-sexuality.
This is far from a comprehensive review of the topic. If you seek a deeper dive, I recommend the works of AF Casy, PS Portoghese, NB Eddy, EL May, P Janssen, Leysen, and Van der Eycken.
As with my other chemical musings, these are finger friendly Morph-Dives into the chem. lit. They're "abbeaviated", but there's enough page flicking to advise protection. Be sure to wear thimbles (or at least lubrication), as thumbs are bound to get pricked. I am not responsible for any paper cuts.

Fundamentals

VOCAB-REHAB

Stereoisomers - isomers with same connectivity; different configuration (arrangement) of substituents
Enantiomers - mirror-image asymmetry; non-superimposable (i.e right-/left-handed morphittens); only differ by the direction (d,l or +,-) of optical rotation
Diastereomers - stereoisomers that are not mirror images; different compounds w/ diff phys properties
Asymmetric Center - tetrahedral carbon w/ sp3 hybridized orbital; capable of σ-bond; (4 different groups attached)
Stereocenter - an atom at which the interchange of two groups gives a stereoisomer
Asymmetric Carbons and cis-trans isomerism are the most common stereocenters
Cis/Trans isomerism - aka: geometric isomerism; applies to orientation of specified groups about a fixed bond, such as a fused heterocyclic morphinan system or an alkene (dbl bond) - cis = same geometric plane; trans = opposite geometric plane; in the morphinan series this refers to fixed constrained alicyclic ring fusions where the amount of rotational freedom is limited
E/Z notation - (E = opposite geometric plane, Z = same geometric plane) Using such notation would make trans-fats become E*-fats* and I don’t believe in furthering the cause of trans-fat bigotry. Thus I will be sticking to the conventional terminology using cis = same side of bond (same geometric plane) and trans to indicate the opposite.
https://i.imgur.com/dNLbPle.png [orbital hybridization chart]
Optically active/Chiral Compound - rotates plane of polarized light in polarimeter (achiral = no rotation) - chiral molec must have an enantiomer
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Stereospecific Binding - SSB - The Hallmark of Morphanity

The μ-opioid receptor (MOR) is characterized by stereospecific binding (SSB). This is not the only G-protein Coupled Receptor (GPCR) that demonstrates SSB, but it was one of the first to be well recognized and is considered a classical model for the SSB of GPCRs.
There are other features that set the MOR apart from other GPCRs, such as the size of the mouth of its ligand binding pocket (active site), which allows it to fit a wide-range of diverse structures including highly flexible acyclic diphenylheptanones (methadone), the high-mol weight (but mostly planar) etonitazene, the atypical bezitramide, spirodecanones (R5260, R6890), and the most rigid and highly-constrained system in the opiosphere, the 6,14-endo-ethano bridged oripavines. (etorphine, buprenorphine). This versatile orifice will be explored later.
Lit Surveys of a number of highly affine ligands with physicochem, IC(50), K(i) data [http://sci-hub.se/10.1016/0014-2999(83)90331-x90331-x)] [https://sci-hub.se/10.1016/0014-2999(77)90334-x90334-x)
The crystalline structure of the murine MOR was elucidated in 2011, the same year I finished grad school. There are new discoveries made every day in this area. It can be difficult to keep track of them all, but the link below contains some of the highlights. The molecular dynamics and mechanics of ligand-receptor interactions and the binding modes of the lig-rec complex are important, but are beyond the scope of this monograph.
https://doi.org/10.1038/nature10954
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stereospecific binding of bioreceptors
https://sci-hub.se/10.1002/ange.19600721806
Stereospecificity, that is, a preferential affinity for one enantiomer over another, depends upon the ligand’s absolute configuration. That is, the 3D arrangement of substituents as they are configured around a chiral center in real life.
As a matter of convenience and convention, the medical and pharma literature uses optical rotatory stereodescriptors when referring to enantiomers. Examples include d-(+)-amphetamine (Dexedrine) or l-(-)-amphetamine (Lamedrine).
The reason that d-amphetamine is more bioactive than its antipode is due to the receptor-preferred absolute config of its asymmetric carbon, which is configured as (S), which means the substituents about the chiral center (as designed by a convention known as CIP Priority Rules) are oriented in a counterclockwise or left-handed direction.
This is the opposite direction that dextroamphet rotates polarized light. D-(+)-amphet rotates light in a clockwise, (+), or right-handed rotation. But its substituents are oriented in a counterclockwise manner according to CIP priority rules, giving it the designation dextro-(S)-amphetamine.
The less active levo-antipode has the (R) abs config, while rotating light to the left or (-).
The optical rotation, in and of itself, does not tell you the abs config about a stereocenter. Nor does the abs config indicate the optical rotation of a compound. Bioreceptors, however, will favor a particular absolute config over another.
Absolute configuration and optical rotation are two separate concepts that are related as they are different ways of classifying stereochemistry, but are not interchangeable. They are measured/determined in different ways.
The most important is absolute configuration. This is the most fundamental property of mol geometry and changes to abs config alters the activity and optical rotation of the molecule. Configuration is determined with spectroscopy.
Optical rotation is an inherent molecular property that can be measured with polarimetry. A pure optical isomer will have a very specific value. The direction and degree that polarized light is rotated by an enantiomer is an important analytical value found in the Merck Index and the anal. chem. lit. Combined with other data, it can be used to identify and characterize optically active products and even identity unknowns.
Left-handed (like me) or counterclockwise rotation is designed levorotatory, levo-, l-, or (-).
Right/clockwise rotation = dextrorotatory, dextro-, d- or (+).
Optical rotation is determined with a polarimeter and polarized light source (typically 589 nm) at a standard temp (listed alongside the [alpha] value in the procedure).
Beyond helping to distinguish enantiomers and analysis of asymmetric products, it is of little use when visualizing the actual spatial arrangement of ligands about a chiral center. For this we need to know the abs config about that chiral center.
The more active enantiomorph is referred to as the eutomer.
It's the one you want in your spoon. As in, “You da man, homie, for hookin’ a brotha/cistenon-gender conformer up w/ da good shiz.”
Examples: l-(-)-levorphanol, cis-(+)-3MF, d-(+)-dextromoramide, etc.
Generally, the eutomer is more euphoric. I was trying to make a mathematics joke involving Euler, but I'm shite at maths and nothing comes to mind.
The less active enantiomer is the distomer.
If it's included with the eutomer this is typically acceptable. An equal mole fraction of enantiomers is referred to as a racemate. A Racemic mixture is not necessarily a bad thing. In fact, it makes you a Mix Master Racemate. Or a Mixture of Ceremonies.
If they want to pay out the nose for Lortabby, go to Walgrabby. If they want reasonably priced mu-tuba goodness, they come to mu-mommy. “Muuu!”
Of course if you sell dextromethorphan (DXM) as white bird (“Heron”), you risk getting a Codone stomp. This is a form of levo-larceny and is frowned upon. (cf. “fentafraud”)
Selling a distomer while claiming it is the eutomer is a sign of disrespect.
Hence the dis in distomer.
The *eudismic ratio is the ratio of the activity of the eutomer over distomer.
Most opioid distomers are essentially inert or low-efficacy ligands that interfere very little with eutomer binding. These have little effect on the bioactivity of the Racemate. But sometimes they have antagonistic effects and/or undesired agonism at another receptor. We will cover case studies (some from my gag reel of personal embarrassment) as we continue.
Reversing the configuration of chiral centers will change the direction of optical rotation. Natural l-morphine has the opposite config of the synthetic d-morphine (the distomer) about it's five chiral carbons.
Simpler molecules are easier to visualize.
Switching the config of the chiral center of levo-(-)-(R)-methadone to the (S)-isomer, will give you the antipode with the opposite optical rotation: d-(+)-(S)-methadone (this is the distomer and has 1/40th the potency of the eutomer).
The eudismic ratio, activity/affinity of eutomedistomer, is approx 40:1 in the case of methadone.
We will see how this works in multi-chiral ligands, such a morphinans later on.
Abs config refers to the arrangement of substituents about a chiral center. This is determined spectroscopically via NMR and crystallography, that is, interpreting scatter-patterns formed by beaming X-rays through a high purity crystal (Scat Pat).
In the organic realm, the chiral carbon is king. Inorganicists (Judas Priests) can concern themselves with the supra-ligancy of (hair) metals. We will stick with the simpler tetrahedral axis of Carbonity.
Official IUPAC nomenclature has adopted a handy convention known as CIP Priority Rules. These were developed by the trio Cahn-Ingold-Prelog. When the nobel laureate trio formed a posse, they played around w/ their initials forming ICP. As such, they became the first juggalos to have been honored with a handshake by the Swedish Sovereign. (seriously, CIP rules are important and there’s a whole load of interesting ancillary backstories/anecdotes that are entertaining - ICP = Insane Clown Possee; for anyone who got that joke, I hope you have better taste in music).
The easiest way to pop one’s stereo-cherry is to start with a single point of chirality: one chiral center, one pair of diastereomers. The simplest chiral opioids are those of the acyclic 3,3-diphenylpropylamines. These highly flexible lipophiles pair strong affinity with favorable lipid solubility.
These are simple molecules with a single stereocenter and a high degree of flexibility, allowing their active species to assume different conformations. The eutomers and distomers of the three ligands reviewed have a variety of optical rotations and abs configuration. They help illustrate the difference between the two stereodescriptors.

Simpler Case-Studies: Single Point Chiralities - Methadone/Isomethadone/Moramide

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P. Janssen - solid-state X-ray crystallographic diagram of methadone/isomethadone
The MOR-active enantiomer of methadone rotates polarized light to the left and is therefore designated as levo-(-)-(R)-methadone. [Acta Cryst., 11, 724 (1958)]
The config around the asymmetric beta-carbon is assigned (R). Crystallography has revealed that the aminopropyl chain of R-methadone exhibits a gauche conformation. [Cryst. Struct. Comμn. 2, 667 (1973); Acta Chem. Scand., Ser. B 28, 5 (1974)]
The aminopropyl chain of the distomer, dextro-(+)-(S)-methadone, assumes an extended conformation. Despite the extended conformation being unfavorable in the ethylketone series, we will see that this same extended conformation is observed in the more active d-(+)-(S)-moramide (below).
Was is das? We also have the μch more euphorigenic (albeit slightly less analgesic; μch higher therapeutic index) alpha-methyl isomer, known as levo-(-)-(S)-isomethadone. The protonated salt has the same guache conformation as protonated l-(R)-methadone. [J Med Chem, 17, 1037 (1974)].
Despite the shared optical rotation of the iso-/methadone eutomers, their chiral carbons are of opposing abs configs l-(S)-methadone vs. l-(R)-isomethadone. Reversing abs config will only cause a reversal of optical rotation in the same molecule. An (S)-molecule X is not necessarily going to have the same dextro/levo-rotation as its structural isomer, (S)-molecule Y.
The methyl positioned immediately adjacent (alpha) to the bulky 3,3-diphenyl ring system, restricts the low-energy conformations available to isomethadone, resulting in its slightly lower affinity and potency compared to the olympian gymnast methadone. [J Med Chem, 17, 124 (1974); J Pharm Sci, 55, 865 (1966)]
l-(S)-Isomethadone is 40 x more active than its d-(R) antipode. This is 40:1 is a similar eudysmic ratio seen in the methadone series as well.
In case that wasn’t confusing enough, let’s throw in the optically-opposite diastereomers of the moramide persuasion.
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3D crystallographic representation of dextromoramide; Tollenaere et al. “Atlas of the Three-Dimensional Structure of Drugs” (1979)
The Moramide eudismic ratio > 10,000. This is the highest recorded ratio in the opiosphere. Featured in a series of opioid diastereomers tested in a MOR affinity study at Janssen involving [3H]-sufentanil displacement, in vitro, rat homogenates, Leysen et al., http://sci-hub.se/10.1016/0014-2999(83)90331-x90331-x).
B/c of their drastic difference in affinity, the moramide diastereomers were a popular set of ligands cited by Janssen in his stereospecific investigations within MOR ligands.
In this study, levo-(-)-(R)-moramide had a K(i) > 10,000 and dextro-(+)-(S)-moramide had K(i) of ~ 1.03.
As you will recall, the less active distomer, d-(S)-methadone, assumes an extended aminopropyl conformation. It is l-(R)-methadone that retains most activity and assumes a gauche configuration. In the moramide series, the opposite is true.
The active eutomer d-(S)-moramide assumes an extended confirmation along the morpholino-propyl axis. (angle -159 deg) The moramide eutomer has both the opposite abs config and opposite optical rotation of the R-methadone eutomer.
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https://preview.redd.it/jjgnp2jevlx91.png?width=2048&format=png&auto=webp&s=117254960ac40737b25ac9f8f7ebcf73ef7594b7
This is reversed (yet again) in isomethadone, where the l-(S)-isomethadone is the eutomer. The abs config is preserved among the isomethadone-moramide eutomers, but the the optics are not. [Act Chem Scand, Ser B 30, 95 (1976); Bull Soc Chim Fr., 10, 2858 (1965); Act Chem Scand Ser B 29, 22 (1975)]
In the rat hot-plate assay, d-moramide has ~ 20 x potency of morphine (sub-Q). The dur of action (rats, s.c.) is slightly longer than methadone. This is decidedly not so in human clinical practice. d-Moramide is noted for a short dur of action (one-fourth methadone) and a high oral bioavail. In man, however, moramide is far less potent than it is in man. [J Pharm Pharmacol, 9, 381 (1957), Postgrad Med J, 40, 103 (1964)]
I’ve highlighted the discrepancies between rodentine-human potencies in prior monographs. Rats are especially insensitive to the effects of 3,3-diphenylpropylamines. For example, The analgesic ED50 in rats is 10-15 mg/kg for methadone (IV). This would equate to ~ 450 mg dose (IV) or a ~ 900 mg dose (PO) in yours truly.
Even if one had an opioid tolerance capable of handling such ratdiculous doses, the HERG inhibition and other non-specific binding would be more than enough to give a Mini-Thinny mouse some Chipmunky Cheeks (squeaks!). The analgesic ED50 dose in rats is equivalent to > 10 x the (estimated) lethal dose in humans. That's mouserageous!
The d-/l- (+/-) and the (R)/(S) stereodescriptors are independent of one another. The absolute configurations of eutomers and distomers, even those closely related within the same chemical class, do not always agree.
I would throw Fisher’s (now deprecated) “Genealogical System” of (Small Caps) D- and L- into the mix, but juggling two systems is difficult enough, a tri-juggle seems like a jug-to-far.
Let’s Juggalo-along, shall we…

Aminotetralin’ Around

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https://preview.redd.it/qmssheswvlx91.png?width=389&format=png&auto=webp&s=c867f8c05af70a2f0d52e0086df1e2a5e835e6d3
While most opioids with a stereo-center will demonstrate stereo-specific binding, there are some interesting exceptions. The above pair of aminotetralin stereo isomers can be thought of as cyclic methadone analogues in which the ethyl ketone moiety has been replaced with a simple methyl group (methadone drawn in the same orientation for comparison). Both of these stereoisomers have the same analgesic ED50, which is on par with pethidine. [J Med Chem, 1973, 16, p 147; p 947]

Novel Ligands 'N Curiosities

This is meant to be a survey of 3D opioid geometries and stereochemistry. But to help wet your novel bespokioid ligand whistle, I will include occasional intermissions highlighting the more unusual and atypical ligands that I’ve encountered during my 14 yrs of exploration. The first is here:
The only “-azocine” that I’ve found worthwhile is the misnomer N-phenethyl 9-(m-hydroxyphenyl) deriv of Anazocine. (despite the shared nomenclature, this has nothing to do with the 6,7-benzomorphans.)(
This is a 3-azabicyclo[3.3.1]nonane (3-ABN), which is akin to a 4-phenyl-4-prodinol with a 3,5-propano bridge gaping the piperidino-divide, m-OH substitution such as that seen in ketobemidone (known to enchance potency in a variety of related compounds; assumed to be analogous to the meta-phenol observed in morphinans) and an unusual 4-methoxy ether at the C(4). The 4-OMe ether is more metabolically stable than 4-propionoxy derivs of prodines (the reversed esters of pethidine). The addition of a 3-Methyl on the piperidine ring stabilizes the 4-propionyl on prodines, making the C(4) less metabolically labile. In a similar manner, the 3,5-propano bridge would be expected to provided steric hindrance and protection against 4-O-demethylation. The m-OH of the phenol can be enhanced further by O-acylation with optimal potency observed by propionyl substitution.
The activity of the N-phenethyl deriv is far less potent in humans than the murine assay suggested (1600 x morphine). The low synthetic yields were the reason that this otherwise worthwhile ligand was only pursued on a single occasion. NIDA dropped interest in using it as a novel opioid receptor probe in the mid 80s. But the Chinese had already been investigating the supra-anazocine derivs since their initial discovery in Japan in the 70s. Much of the Chinese literature of that area remains accessible only at University Archives, which, during my years in grad school, I was able to take full advantage of the opportunity to compile a substantial dossier of literature on this series. In spite of NIDA's unenthusiastic pursuit of a proper SAR elucidation of the series, the Chinese developed over 10,0000 different derivatives and as of today, continue to investigate the series in through the patent literature, hinting that the unique properties of the class may make for marketable research probes that could be commercially useful for opioid research.
The most unique property among some of the optimal Chinese variants is the incredible affinity that these super-agonists have for the MOR. Using CHO assays, the Chinese observed that several derivs strugggled to be displaced by radiolabelled [3H]-lofentanil and [3H]-ohmefentanil. Some required three washings and three successively more cocentrated titrations of [3H]-lofentanil in order for the agonists to be displaced from the receptor. As a full agonist with a Sodium-Index of unity, Lofentanil is unique among agonists, and is believed to form the lowest engergy ligand-receptor binding complex of any kown opioid.
Additional surprises were the fact that nearly all of the Chinese derivs were potent Kappa-antagonists. But that they also had very high therapeutic indices. In several ligands, doses up to 2000 x the therapeutic ED50 analgesic dose were required to depress the rodent's respiration rate by 33%. I'm not sure why they chose to report these ratios in the way they did, except to say that alot of this was done back in the 80s, and many testing and pharmacology standards that we use in the west had not yet been standardized in the Chinese literature.
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Substituted Anazocines; the N-phenethyl deriv is one of the more atypical ligands I’ve personally investigated
If you want to get the skinny on this lusty ligand, you’ll have to ball-N-stick around until the end. If you’re ready to get your mind blown, allow me to get down on my kneepads and start the show.
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Morphy’s I’d Like to Spoon

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14(R) cis-B:C fused morphinans [levorphanol featured] - T-shaped Barrel Plug orientation
This is my favorite graphical representation that helps demonstrate the varied geometries of the many morphinan geometric isomers. The above figure (representing levorphanol) is often called the "T-shaped Barrel Plug" orientation.
The elucidation of the absolute configuration of natural l-morphine allowed for several assumptions to be made about the abs config about the shared analogous stereocenters of other morphinans and 6,7-benzomorphans. These configuration-activity relationships held (mostly) true across the conformationally rigid bonds that compose the morphinans and 6,7-benzomorphans.
The morphinan superfamily consists of three subgenres + closely related 6,7-benzomorphans.
These four polycycles, sometimes referred to as the classical polycyclic opioids, are easily grouped by the number of adjacent fused rings in the system:
Hexacycles: 6,14-endoethano bridged tetrahydrooripavines (Bentley compounds) - semi-synthetic, Diels-Alder adducts of Thebaine [AF Casy, Opioid Analgesics (1986), Chap 4] - KW Bentley discovered these useful Diels-Alder adducts of thebaine and oripavine while working at Reckitt-Benkister and found that the diene system of thebaine was compatible with a plethora of dienophiles.
Pentacycles: 4,5-epoxymorphinans (morphine, oxymorphone) - semi-synthetics, w/ the chracteristic 4,5-epoxymorphinan ring, derived from the three major alkaloids (morphine, codeine, or thebaine) https://sci-hub.se/10.1055/s-2005-862383
Tetracycles: synthetic morphinans (racemorphan, DXM) - fully synthetic, derived from Grewe Cyclization of 1-benzyloctahydroisoquinolines (octabase) [their chemistry along with that of the benzomorphans has been thoroughly reviewed by Schnider et al. in “Organic Chemistry, Vol. 8: Synthetic Analgesics, Part IIa” (1966)]
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https://preview.redd.it/mgd59eilzpx91.png?width=1803&format=png&auto=webp&s=360e71e63a0f2a531a277f3770e835a48f1958ae
Tricycles: 5,9-disubstituted 6,7-benzomorphans (phenazocine, pentazocine, metazocine; all clin relevant derivs are of the 5,9-dimethyl variety) - fully synthetic; a variety of synthetic methods are available, but some of the most efficient use a Grewe Cyclization-mimetic strategy [chemistry reviewed by Palmer, Strauss, Chem. Rev. 1977, 77, 1; orig synth by Barltrop, J Chem Soc 1947, 399]
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https://preview.redd.it/0cnl7t320qx91.png?width=1672&format=png&auto=webp&s=e0bbaadd74f7b2513b34d92d422f4675f74d4616
While 5,9-disubstituted 6,7-benzomorphans are often treated as a separate class, they are included here. The benzomorphans C5 and C9 correspond to C14 and C13 in the morphinans. These analogous carbons shares the same cis/trans structure-activity relationships that are present in the morphinans.
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https://preview.redd.it/okp02ev80qx91.png?width=1312&format=png&auto=webp&s=72440fbcfaa706d1d8c03722652c72e8aba1418a
[The all-carbon stereocenter, corresponding to C13 of the morphinan scaffold (red), is shared among all three morphinan subgenres. The 5,9-disubstituted 6,7-benzomorphans (phenazocine) contain an analogous all carbon center at C5 (same relative position; diff numbering). The unsubst- and 9-mono-substituted benzomorphans lack this feature and are of much lower potency]
The morphinans share a common 5,6,7,8,9,10,13,14-ocatahydrophenanthrene core, as well as much of the same configurational asymmetry (see below). Other than the additional E-ring (formed by the 4,5-ether bridge), the key differences between the three subtypes are variations of the C-ring.

4,5-Epoxymorphinans

Natural l-(-)-Morphine is a T-shaped pentacycle with a central 4-phenylpiperidine (highlighted in bold in figure below) shared with other polycycles and some monocyclic opioids
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https://preview.redd.it/33lzzxap0qx91.png?width=2048&format=png&auto=webp&s=75208ebb9eeebb1f96234f63bfb180436415c5aa
Morphine w/ official numbering and rings A-E. The 4-phenylpiperidine core in bold (derived from Rings A + D). The five chiral centers are the bold dots. Note the cis-octalin arrangement of the B:C rings. The C:D rings assume a trans-octahydroisoquinoline arrangement. The cis- and trans-orientation are explained in next section.
The above model is accurate for other 7,8-unsaturated derivs, i.e. codeine, nalbuphine. The partial boat conformation of the C-ring differs from the fully saturated morphinans, (hydromorphone, oxycodone, etc) which have C-rings that conform to the receptor-favored chair conformation.
A brief summary of the boat/chair geometries of the morphinan nucleus is provided in later sections of this monograph.
More in depth discussion of this is avail from J Chem Soc (RSC), 1955, p 3261; Acta Cryst 1962, 15, 326; Chem Pharm Bull, 1964, 12, 104; Eur J Med Chem, 1982, 17, 207, Tetrahedron, 1969, 25, 1851 (trans-B:C fused isomorphine); the latter 3 refs are based on more modern H-NMR, which reached the same conclusions as the earlier crystallography studies).
The five asymmetric carbons of naturally occurring l-(-)-morphine possess the following absolute configurations: C5 (R), C6 (S), C9 (R), C13 (S), C14 (R).
[See the appendix for a brief overview of the CIP Priority Rules that govern these designations; Cahn, Ingold, Prelog - Experientia, 1956, v 12, p 81]
The N-CH3 group is oriented equatorial. The 7,8-double bond causes ring C to assume a half-boat conformation, w/ C6, C7, C8, and C14 lying ~ in the same geometric plane. The three hydrogens at 5-H, 6-H, 14-H are oriented cis, while 9-H is oriented trans. [G. Stork - “The Alkaloids, Vol VI” (1960) p 219; KW Bentley “Chemistry of Morphine Alkaloids” (1954); “The Alkaloids, Vol I” (1956); D. Ginsberg “The Opium Alkaloids” (1962)]
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Alternative view of morphine with expanded C-ring shown in the half-boat conformation, w/ the cis-(1,3-diaxial) fused piperidine shown in a perpendicular geometric plane
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All of these terms and geometries are reviewed in further detail in later sections.
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https://preview.redd.it/mefj5am71qx91.png?width=2048&format=png&auto=webp&s=abac15edcb1201336020410b575196fe55400a27
[natural l-(-)-morphine and its mirror-image enantiomer d-(+)-morphine. Diagram of the basic 3-point receptor model proposed by Beckett & Casy in 1954. The simple Model held true for many decades with little revision and was still being cited in several reviews from the 1980s and 90s. (J Pharm Pharmacol 1954, v 6, p 896; ibid. 1956, v 8, p 848; AF Casy “Opioid Analgesics” (1986) p. 474) (other receptor models developed after the Beckett-Casy postulate include an interesting clay-plaster mold by Martin - https://archives.drugabuse.gov/sites/default/files/monograph49.pdf
The five stereocenters of the inactive d-(+)-morphine are oriented in the exact opposite configuration: 5-(S), 6-(R), 9-(S), 13-(R), 14-(S). [Gates, JACS, 1952, 74, 1109; ibid. 1956, 78, 1380; ibid. 1954, 76, 312]
[Seminal work on morphine stereochem: J Chem Soc, 1955, p 3261; p 3252; Helv Chim Acta 1955, 38, 1847]
Using the 2n formula (n = # chiral centers), 25 = 32 theoretical stereoisomers. Geometric constraints on the morphinan system reduce that number by half (16 isomers). These geometric constraints are due to a number of ring fusions in the morphinan nucleus.
The structure and functional groups attached to the C-ring vary widely among the 4,5,6-ring morphinans. As a result, switching the key ring fusions have a variety of effects on bioactivity and the safety profile of the isomer. Juxtaposition of the cis-B:C rings at the C13-C14 bond results in trans-B:C fused isomorphinans. This is reviewed more thoroughly in later sections.
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geometries of cis-B:C fused morphine/levorphanol compared to trans-B:C isolevorphanol
[commentary on Multi-Chiral Molecules (such as morphine) is provided in the comment section]
Despite the hella complicated enantiomeric zoo brought about by five stereocenters, morphine, has rather straightforward chemistry. This is thanks to a series of ring-fusions inherent in the morphinan system.
Get ready for some epic Ring Fusion Morphanity...