Time to yap…
Sources: DATBooster and Bootcamp (got half price on both because I qualify for financial aid).
Bootcamp for bio, gen chem, QR, PAT, and RC. Booster for orgo + extra practice tests + paranoia I didnt get enough practice from bootcamp
Timeline: Tried to study last November but couldn’t stay on track bc I am a massive procrastinator lol. Wanted to start again this January but went through some crazy heartbreak....... 💔😭. So I actually started in February and studied for about 10-11 solid weeks. Was VERY on and off about studying but I still worked really hard.
Background: Junior with a 3.96 gpa. Was shadowing/volunteering and research, but class load was easy. HOWEVER I do wanna say I didn’t remember any of the sciences I took tbh. I genuinely learned all this content from scratch. Every reaction and fact I memorized was through my own hard work.
I ALSO NEVER TOOK A TRUE FULL LENGTH EXAM. I utilized practice tests as question banks so I would not freak out. Timing honestly is not something I believe needs to be worked on (other than PAT lol) because at the end of the day, it is a content exam. Either you know it or you don't. **This is only for those that are severe overthinkers btw ***
PAT-17: Absolutely no advice from me, I suck at this. Just practice and you'll eventually see it ig...idk.
BIO-24: Went through the high yield bootcamp notes, only watched videos if necessary. Did all bio bites and q banks, but a month out I realized I didn’t retain anything. So instead, I created an 1800 card anki deck of the entire Bootcamp high yield notes. Took around 8-10 days, then I went through them every day. This helped WAY more than reading and highlighting the notes and doing bio bites in my opinion. ALSO, I swear I had 5-6 questions exactly from boostebootcamp practice exams. Burn the facts into your brain.
Gen chem-24: Watched Dr. Mike videos which were solid. Did all the qbanks but they're unnecessarily difficult in my opinion. Have the basics down (periodic trends, balancing reactions, all formulas..etc). Learned a lot from practice tests tbh. Chads videos were good too.
Orgo-30: Learned EVERYTHING from scratch bc orgo at my school was online so i didnt learn anything. Booster's notes CHADS VIDEOS are superior. Honestly, I did NOT like Dr. Mikes bootcamp orgo videos. I know a lot of ppl like them, but it never stuck. Also, bootcamp DOES NOT have enough questions to practice. Booster has like 80 for each chapter while bootcamp will have like 20-30 or something. So I am grateful I had booster, but if you can't afford both, use chads videos and just do practice exams from whichever course you purchased. ALSO REACTION BITES ARE A MUST. Although my exam had like 3 reactions, I was able to recognize every reaction in a heartbeat. But MOST IMPORTANTLY, KNOW THE BASICS (Aromacity, S, Isomers, O/P meta, acid/base, hybridization, bond length) and understand it conceptually through practice tests.
QR-21: Started practicing 2 weeks out, just did all 10 bootcamp tests and learned from those. Saw some questions that were the exact same. Know your formulas, and it was SO MUCH more simpler on the real test. Even after my first 7 practice tests I was so confused with the word problems and statement questions, but you'll eventually see a trend and it will be easier on the exam most likely.
RC-22: Also started 2 weeks out. For every practice section, I would read the passage then answer questions. But when I started the actual test, I spontaneously switch to search and destroy. I looked at the first few questions and found them directly IN ORDER. So I just kept going and finished with 10 min left. On practice tests, although I did consistently decent, I would run out of time. So jus relax your eyes and dont freak out. Not all questions were in order, but MOST were. There were a couple author's purpose questions but at that point, you get an overall idea of the passage.
Practice tests: Made anki cards on all questions I even had to second guess on, even if I got them right. Just make a card and do them the next day. Then continuously do them until test day. Read/watch the reviews and understand WHY that answer is that answer. There has to be a reason, figure it out...
With that being said, YOU ARE SMART ENOUGH I PROMISE. Anyone can do it, you just have to discipline yourself and understand that if you want it, you GOTTA go get it.
I know ppl have studied for this test and went through far worse, but dealing with a heavy heart and studying for this exam is not easy. Please take breaks and take care of your mental health. NO EXAM determines who you are as a human and who you impact in your lives. If ANYONE has any questions, don't hesitate to DM me.

hey guys, does anyone have any idea how to do question d.) To find isomer 1 ans 2 The second slide is my attempt at drawing one of the isomers. I like nmr but I hate that this question has mixed isomerism with nmr. Any help would be amazing T_T

Does anyone have horror stories from using the Bens Deet 100?
For instance, my dad left a bottle of it in the side compartment on his truck door, it leaked and ate the clear coat and paint straight down to the bare metal.
I had a cheap pocket knife given to me by my employer in the side compartment of my car and I had a bottle of Deet 100 leak and essentially liquify the plastic handle on the knife.
Both of these leaky bottles were sealed and appeared to leak from pressure overtime. I learned the hard way to never accidentally leave that stuff in my car.

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

---------------------------------------------
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:
​
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.
—---------------------------------------------------------------------------------------------------------------------
Karma is a Benzimidazole, who doesn't play with balls (Deandra’s Version)
​
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.
​
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.
​
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]
​
[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]
​
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]
------------------------------------------------
History
​
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
​
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.
​
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.
​
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.
​
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).
​
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.
—---------------------------------------------------
Enter Nitazene…
​
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.
​
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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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]
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To read the full version of this article, visit Patreon.com/Oxycosmopolitan

Coordination bond isomerism, often called linkage isomerism, is a structural isomerism found in coordination compounds. Coordination compounds are molecules or ions of ligands surrounding a core metal atom or ion. Ligands are molecules or ions that can contribute electron pairs to a central metal atom or ion, resulting in coordinate covalent connections.
Coordination bond isomerism occurs when the ligands' connection to the central metal atom/ion differs between isomers. This causes the development of various coordination entities, even though the molecules or ions contain the same types and amounts of atoms. The isomers form as a result of ligands attaching to the metal atom/ion via various atoms or different donor atoms within the same ligand.
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To understand coordination bond isomerism better, let's delve deeper into the concepts involved:
Coordinate Covalent Bonds: In coordination compounds, coordinate covalent bonds are established between the central metal atom/ion and the ligands. In these bonds, one of the atoms (typically a ligand) gives a pair of electrons to the metal centre, forcentre shared electron pair.
Ligands: These are molecules or ions that form coordinate covalent connections with the core metal atom or ion. Ligands are classed according to their donor atoms and coordination number, the number of atoms directly bound to the core metal atom or ion.
Coordination Number: A metal ion's coordination number in a complex is the number of ligand donor atoms to which it is directly bound. Coordination numbers 2, 4, and 6 are commonly used, however other numbers are also available.
Isomerism: Isomerism is the phenomenon in which two or more chemical compounds have the same molecular formula but distinct configurations of atoms or bonds, resulting in different chemical or physical properties.
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Types of Coordination Bond Isomerism:
Cis-trans Isomerism: This sort of isomerism is found in coordination compounds with coordination numbers of four or six. Similar ligands are contiguous in cis isomers but opposite in trans isomers.
Linkage Isomerism: This sort of isomerism occurs when the ligand can attach to the central metal atom or ion via several atoms. The atoms used to coordinate the ligand to the metal centre differ between the two isomers. Common ligands with linkage isomerism include nitrite (NO2-) and nitro (NO2-) groups, which can bind through nitrogen or oxygen atoms.
Coordination Position Isomerism: Coordination position isomers differ in the manner in which the ligands are linked to the central metal atom/ion. This can happen when there are multiple potential locations on the ligand molecule for coordination with the metal centre. In complexes with bidentate ligands, for example, the ligand can coordinate with the metal centre via several donor atom sets.
Significance of Coordination Bond Isomerism:
Structural Diversity: Coordination bond isomerism broadens the structural variety of coordination compounds by allowing the production of several isomers with different geometries and characteristics.
Tuning Reactivity: Because of their distinct structures, different isomers of coordination compounds may display varying reactivities. This can be used in catalysis and other chemical reactions.
Biological Relevance: Coordination bond isomerism is important in biological systems involving metal ions, such as metalloenzymes and metalloproteins. Understanding the many isomers generated by coordination chemicals can provide insight into their biological roles and interactions.
To summarize, coordination bond isomerism is an important element of coordination chemistry in which coordination compounds can exist as several isomers with the same chemical formula but different ligand configurations around the central metal atom/ion. This effect increases the structural variety and reactivity of coordination compounds, which has consequences in chemistry, biology, and materials research.

Summary: Researchers made a significant breakthrough in understanding how ketamine treats depression-related social impairments, focusing on the drug’s effects in the mouse model.
Their study shows that (R)-ketamine, as opposed to (S)-ketamine, effectively restores neuronal activity in the anterior insular cortex, a region crucial for emotional regulation and social cognition. By treating mice subjected to chronic social isolation with (R)-ketamine, the team observed improved social interactions and cognition, attributing these enhancements to the revitalization of the anterior insular cortex.
This discovery underscores the potential of (R)-ketamine in treating social impairments associated with depression, suggesting a targeted approach to improving mental health and well-being.

Key Facts:

1. (R)-ketamine vs. (S)-ketamine: The study differentiates the impacts of these two enantiomers of ketamine, finding that (R)-ketamine uniquely reverses decreased neuronal activation in the anterior insular cortex caused by social isolation.
2. Improved Social Cognition: Mice treated with (R)-ketamine showed enhanced ability to recognize social cues, a key indicator of improved social cognition and interaction.
3. Crucial Role of Anterior Insular Cortex: The positive effects of (R)-ketamine on social impairments are linked to its ability to restore function in the anterior insular cortex, highlighting the importance of this brain region in emotional regulation and social behavior.

Source: Osaka University
Well-being is important for everyone, especially when we feel lonely or isolated. Depression is a serious challenge for many people and finding an effective solution is key.
In a recent study published in Molecular Psychiatry, researchers from Osaka University used a mouse model of depression to reveal that one form of ketamine (a common anesthetic) in low doses can improve social impairments by restoring functioning in a specific brain region called the anterior insular cortex.

Moreover, when neuronal activity was suppressed in the anterior insular cortex, the (R)-ketamine-induced improvements disappeared. Credit: Neuroscience News

Ketamine is often used at low doses to treat depression, but its actions in the brain remain relatively unclear. Generally, ketamine refers to a mix of two different forms of ketamine: (S)-ketamine and (R)-ketamine. These two molecules are mirror isomers, or enantiomers—they have the same molecular formula, but their three-dimensional forms are mirror images of one another.
Although they usually occur as (S) and (R) pairs, they can also be separated into either (S)-ketamine or (R)-ketamine. Each is beneficial in treating depression, although their specific effects vary.
When the research team decided to test the effects of (S)-ketamine and (R)-ketamine on depression-like symptoms in mice, they first had to decide on an appropriate model. Given that depression and social impairments can be induced by long-term social isolation, they chose a chronic (at least 6 weeks) social isolation mouse model.
The researchers then used a method that allowed them to directly compare neuronal activation throughout the entire brains of mice treated with (S)-ketamine, (R)-ketamine, or saline (as a control) directly after behavioral tests.
“In this way, we were able to observe differences between (S)-ketamine and (R)-ketamine treatments in terms of neuronal activation across the whole brain, without having a predefined hypothesis,” says lead author of the study Rei Yokoyama.
“Notably, we found that chronic social isolation led to decreased neuronal activation in the anterior insular cortex—a brain region that is important for emotional regulation—during social contact, and that (R)-ketamine, but not (S)-ketamine, reversed this effect.”
The researchers also found that mice treated with (R)-ketamine were better at recognizing unfamiliar versus familiar mice in a social memory test, indicating improved social cognition. Moreover, when neuronal activity was suppressed in the anterior insular cortex, the (R)-ketamine-induced improvements disappeared.
“These findings highlight the importance of the anterior insular cortex for the positive effects of (R)-ketamine on social impairments, at least in mice,” says Hitoshi Hashimoto, senior author of the study.
“Together, our results indicate that (R)-ketamine may be better than (S)-ketamine for improving social cognition, and they suggest that this effect is dependent on restoring neuronal activation in the anterior insular cortex.”
Given that the rates of social isolation and depression are increasing worldwide, these findings are very important. (R)-ketamine is a promising treatment for isolation-induced social impairments and may contribute to a better quality of life in people with associated disorders.

About this psychopharmacology and depression research news

Author: [Saori Obayashi](mailto:gi-strategy@cgin.osaka-u.ac.jp)Source: Osaka UniversityContact: Saori Obayashi – Osaka UniversityImage: The image is credited to Neuroscience News
Original Research: Open access.“(R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice” by Rei Yokoyama et al. Molecular Psychiatry
Abstract
(R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice
Chronic social isolation increases the risk of mental health problems, including cognitive impairments and depression. While subanesthetic ketamine is considered effective for cognitive impairments in patients with depression, the neural mechanisms underlying its effects are not well understood.
Here we identified unique activation of the anterior insular cortex (aIC) as a characteristic feature in brain-wide regions of mice reared in social isolation and treated with (R)-ketamine, a ketamine enantiomer.
Using fiber photometry recording on freely moving mice, we found that social isolation attenuates aIC neuronal activation upon social contact and that (R)-ketamine, but not (S)-ketamine, is able to counteracts this reduction. (R)-ketamine facilitated social cognition in social isolation-reared mice during the social memory test. aIC inactivation offset the effect of (R)-ketamine on social memory.
Our results suggest that (R)-ketamine has promising potential as an effective intervention for social cognitive deficits by restoring aIC function.

Source

• Neuroscience News (@NeuroscienceNew) [Feb 2024]:

(R)-ketamine, unlike its counterpart (S)-ketamine, can notably improve social impairments in mice by rejuvenating the anterior insular cortex, a critical area for emotional regulation.This study underscores the nuanced differences between the enantiomers of ketamine in treating depression-related symptoms.
The findings demonstrate that (R)-ketamine, administered in low doses, not only enhances social cognition but also requires the activation of the anterior insular cortex to exert its beneficial effects.
This research paves the way for (R)-ketamine to become a promising solution for social isolation and depression, potentially offering improved quality of life for affected individuals.

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• Depression Ketamine

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does anyone know how to answer this question

How would I do part b?
I think a double bond is formed on the fifth carbon, as the bond between the sixth carbon and OH breaks, but what happens then to the OH? Where would it go (I know in the question it doesn't ask this, but I want to understand)

So My question is what I am supposed to to do with this formula? Like I am just adding an extra 2 hydrogens to every alkane i see?

In questions where they ask us to draw the structures but they don't mention any specific type, Do they give mark for structural formula's rather than skeleton (In the MS only skeleton is drawn).
For example: 9701 S23 QP 22 Q5bii
A and B are structural isomers with C5H10O as the formula's