Based on this research on Pan Cyan Alkaloids when mushroom material is stored dry for 4+ months, a large part of the psilocybin breaks down into psilocin:

In our case 65% of the psilocybin broke down (dephosphorylized) into psilocin within the 4 month period. It made very little difference if the mushrooms were in powdered form, whole form, stored with argon, or without argon!

However the total amount of psilocybin + psilocin / potency is not drastically changed:

What does this mean? When properly dried (cracker dry) and stored in sealed glass jars at room temperature and out of light, after four months in storage the mushrooms were nearly as potent as the day they were put into the jars. There was only a 4% loss of potency in the sample stored in powdered form with argon. In the worst case, there was a 9% loss of potency in the sample stored in powdered form without argon and a 5% loss of potency in the sample stored in whole form without argon.

Reading that, I figure there are maybe two "strategies" for creating an end product of active mushrooms:

• Always use the freshest dry mushrooms you have, because it has the highest overall potency (although apparently at 6 months dry material only loses 5-10%).
• Make what I'm calling a "Party Mix" of that species/strain. i.e. Using a) some of your "freshest" dry material and b) some material which is older, maybe 4-8 months since dried.

In a nutshell, the "Party mix theory" (or tek, if you prefer...), would be to mix up approximately equal parts "fresher" dry mushroom, with "aged" dry mushroom. The goal would be to approximately equalize the amounts of psilocin and psilocybin, to account for variances in "affect" among a diverse group of potential consumers.

Note: I originally posted this in r/mushroomgrowers, because obviously there is a cultivation part of this (you'd need to time your cultivation cycles, to achieve what I'm suggesting...) but it was removed with "this is not a drugs subreddit, it is a cultivation subreddit", so reposted, here.

1. Cucurmin/Longvida (400mg)

Rational: Agonist-induced nAChR desensitization occurs rapidly, and among nAChR subtypes, α7 nAChR desensitization is the fastest.

Cucurmin is a type II positive allosteric modulator (PAM-2) of the nAChR subunit a7.

type II PAMs reduce the likelihood of agonist-induced α7 nAChR desensitization, thus providing a tool for escaping tolerance and overdose

type II PAMs delay receptor desensitization, reducing the energy barrier. These PAMs can also result in destabilization of the desensitized state of α7 nAChRs, allowing rapid restoration of ion channels in active conformations.

Type II PAMs do introduce the possibility possibility for Ca2+-induced cytotoxicity (cell toxicity) but curcumin attenuated nicotine-induced apoptosis, oxidative stress and inflammation; while elevating P-CREB and BDNF levels. Thus, curcumin via activation of P-CREB/BDNF signaling pathway, confers neuroprotection against nicotine-induced inflammation, apoptosis and oxidative stress.

The Neuroprotective Effect of Curcumin Against Nicotine-Induced ... - PubMed

Figure 12. α7-PAMs from natural sources. https://www.mdpi.com/1420-3049/28/3/1270

Curcumin is suspected to be able to protect against cardiac hypertrophy, inflammation, and thrombosis. This inhibition has been shown to prevent heart failure in female rats (examine research breakdown).

Appears to hold protective effects on blood vessels.

Supplementation of curcumin to a prediabetic population over the course of nine months appears to preserve pancreatic function and improve both insulin sensitivity and adiponectin relative to control, and curcumin was able to prevent any occurrence of diabetes during this time frame (whereas 16.4% of control developed it) (examine research breakdown).

https://examine.com/supplements/curcumin/research/#OQgaRlD-neurology_OQgaRlD-dha-concentration

people who smoke cigarettes are 30%–40% more likely to develop type 2 diabetes than people who don't smoke.

Smoking and Diabetes | Tips From Former Smokers | CDC

2. Taurine (3,000mg)

prevents nicotine-induced cardio toxicity and attenuates the reduction in hormone synthesis observed in rats (Nicotine, in rats, reduces the production of testosterone, LH, FSH, and increases prolactin).

Conversely, a significant increase in testosterone and free testosterone has been observed in smokers. In a practical setting, this may be sufficient evidence to conclude that nicotine does not reduce testosterone production in humans.

Taurine, the most abundant free B-amino acid in the male reproductive system, possesses antioxidant properties, protecting against oxidative stress-induced testicular dysfunction.

Furthermore, it boosts blood flow and decreases blood pressure.

3. Nicotine

A. Nicotine gum (1-2mg) Sublingually B. Nicotine patch (15mg)

Rational: The speed at which nicotine reaches the brain and the overall concentration of nicotine that reaches the brain are predictors of the addicting potential of nicotine, with high doses and fast absorption (cigarettes) being more addictive than slower release forms (gum, patches)

Starting at 2pm PDT and going until late this evening, our main servers will be down. I tried to post this to r/drugs but it got mod-deleted. Seems related to me, thought someone might ask. Hope it fits in DrugNerds?

It's been 10 years since the last time we had to take our main servers down. But we had to move physical data centers for complex reasons, so this requires physically moving our owned hardware to Santa Clara from South San Francisco. Machines are now offline, packing up the PDUs, the firewall appliance, etc and then driving them to new location!Always an unknown when old hardware that's been running so long gets fully powered off or if we'll have trouble with the networking config at the new location...

Everything back up and working now in the new data center as of around 5pm. Hurray!

Service interruption complete.

Since there's very little data available on this topic we ( me and u/akuli112 ) have tried to abstract it from the closest compounds that are available in both triazolo(-OLAM) and diazepine(-EPAM) forms.

The closest one metabolically are flubromazepam and flubromazolam which are also conveniently analogues of bromazepam and bromazolam respectively.

The data for the fluoro analogues are deducted from ~10 different studies and case reports.Elimination time = 5 half-lives of the compound, at which point 96% or less of the substance can be found in blood.

Calculation table:

----------------------------------------------

Flubromazolam - 28h half life

hydroxyflubromazolam - 38h (x 1,35 parent compound half-lives)

Elimination time (ESTIMATE): 190h (8 days)

Flubromazepam - 106h (3,78x longer then Flubromazolam)

hydroxyflubromazepam - 134,4h (x 1,26 Flubromazepam half-life)

Elimination time (ESTIMATE): 670h (28 DAYS)

--------------------------------------------------

Speculation to bromazepam / bromazolam, with relevant clinical data and some assumptions you can recalculate back to this:

bromazepam - 17h

hydroxybromazepam - 20h (x 1.2 bromazepam half life)Elimination time (estimate): 100h (4 days)

bromazolam: 3.8h (0.22x the time of the -pam compound which makes bromazepam last around 4,4 longer then bromazolam)

hydroxybromazolam: 5h (x 1.31 bromazolam half life)

Elimination time (estimate): 24-26h (1 day~)

------------------------------------------------------

You can also confirm this by taking the elimination times of the fluoro analogues + metabolites (670/190)= 3.5 (flubromazepam lasts 3.5x longer then flubromazolam) and (100/26) = 3.8 (bromazepam lasts 3.8x longer in the blood then bromazolam).

This would mean that bromazolam with its main metabolite stays in your system for around 25 hours, at least.

We also considered that bromonordiazepam (desalkylgidazepam) might be a better comparison for bromazolam then bromazepam would be. Applying our calculation here, without accounting for bromonordiazepam metabolites such as the hydroxy and glucoid metabolites, because we couldn't find data for them.

bromonordiazepam: 86.7h (half-life)

Elimination time (estimate): 432,5h (18 days)

Using factor 3.78 from our flubromazepam to flubromazolam comparison.

bromazolam (86.7 / 3.78) = 22,93h

Elimination time (estimate): 114,68 (~5 days)

The lower elimination time deduced from bromazepam could be correct, as the tetrazole ring in -azolams is also susceptible to hydrolysis. But it is possible that the cyp enzyme activity increases further when switching from two to one halogen substitunent. Either way in both cases, the lactam is hydrolyzed well before the pyridine or benzene ring is attacked.Any feedback by people with more in-depth pharmacological knowledge would be welcome!

Sources:

https://doi.org/10.1002/jms.3279

https://doi.org/10.1093/jat/bky039

https://doi.org/10.1002/wfs2.1416

https://doi.org/10.1093/jat/bkaa043

https://doi.org/10.1002/dta.2211

https://www.who.int/docs/default-so...es/43rd-ecdd/final-flubromazolam-a.pdf?sfvrsn

https://bradscholars.brad.ac.uk/bitstream/handle/10454/19320/bkad004.pdf?sequence=2&isAllowed=y

Structure-Activity Relationships of the Benzimidazole Opioids: Nitazenes and Piperidinylbenzimidazolones (Cychlorphine, Brorphine, Bezitramide Derivs) - [Vol 1: 2-Benzylbenzimidazoles]

By: Oxycosmopolitan

X.com/DuchessVonD

Patreon.com/Oxycosmopolitan

u/jtjdp

r/AskChemistry

​

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. Whether you are considering the class for its activity at the nociception (NOP) receptor or the μOR (or as a dual-ligand), there is plenty to like about the class.

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 related to his blockbuster haloperidol. 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 prototypes. 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 (i.e. 4-phenylphenampromide Wutampiram***, Wutampromide)***:

[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 fumble balls (Taylor’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://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://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-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]

[https://i.imgur.com/dF1ZnXz.jpeg]

[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)]

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://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 3,3-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/user/jtjdp/comments/11jbjmy]

---------------------------------------------------------------

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://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 and morphinan chemistry, see my reddit post: [https://www.reddit.com/r/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 6-, 5-, 4-, and 3-ring morphinan superfamily, see my reddit post: Morphinan History X [https://www.reddit.com/r/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.

[https://i.imgur.com/epFABkr.jpg]

While the proposed pharmacophore held a humbler 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 mâché. 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.

[https://i.imgur.com/hEjeDlg.jpg]

The following core structural features were determined to be essential for strong analgesic activity:

An aromatic ring system: provides a platform for π-π stacking interactions with amino acid residues at the μ-receptor active site.

The aromatic ring is attached to a quaternary carbon.

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.

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://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…

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://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].

[https://i.imgur.com/WEhPd6w.jpg]

For the rest of this article, please visit my Twitter at:

https://X.com/DuchessVonD/status/1766725654148518330

More of my musing related to the medicinal chemistry of opioids are available at Patreon.com/Oxycosmopolitan and u/jtjdp

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