Novel Opioids

[Fertile]

very interesting, like the well know case of Thalidomide

That is my fear.

It turns out that while we knew nitrazepam, nimetazepam, flunitrazepam & clonazepam could cause liver damage, it turns out that nitrazolam and flunitrazolam are just as toxic with reports of severe liver injury.

But the thing is that it's been known since the 1970s that nitrobenzodiazepines were more toxic than other benzodiazepines, it took until 2017 for someone to identify the specific metabolite. I turned out to be:

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Image 2 hosted in ImgBB

ibb.co

Now, you can see that it doesn't matter about the rest of the scaffold. That 7-nitro (or 8-nitro for 4-ring benzos), their is an enzyme system that WILL reduce that -NO2 to an NH2. The hydroxylation (oxidation of the amine) is actually minor REDUCTION so we are not considering large amounts of this species.

But it can and has killed - a LOT.

That is why I stick to the modification of known opioids and only introduce modifications as and when needed .Even then I stick to modifications which have a VERY proscribed metabolic pathway.

As an example, mephedrone is VERY safe because that 4-methyl (p-methyl) represents a really good metabolic pathway. Almost 100% of mephedrone undergoes oxidation at that point. First to the aldehyde (via non-specific blood enzymes) and then to the carboxylic acid which will readily form addition salts and be eliminated...

That's why when people place a halogen or pseudohalogen at the para (4) position of the benzene, their will be 8 or 9 minor metabolic pathways and who knows if one of them produces a toxin?

Thalidomide was a really subtle one. Originally the patent called for the (S) isomer (the active enantiomer) but it turned out that the human body inverted that chirality ant it's the (R) isomer that turns out to produce intercalation (insertion into the DNA during cell multiplication). If that sounds horrific, it IS.

So a very good point to make.

IF I need a ring-substitution, methyl is the first one I look at. Then maybe a longer alkyl, methoxy or thiomethoxy BECAUSE the body can metabolize them. If you place a halogen of pseudohalogen then the body cannot alter it. The presence of that (pseudo)halogen also means the body cannot oxidize the ring at the carbons adjacent to that group... so as an example, if you add a p-Br, the entire ring cannot undergo metabolism.

That is why I designed over 50 novel compounds in 2 years an in total only 7 reached market. And people in drug development would be pretty impressed because a 20% lead to produce is REALLY hgh.

I think you might enjoy looking at Paul Janssen's work.

Janssen Pharmaceuticals - Wikipedia

en.wikipedia.org

R5 then R79 then R252 then R516. Do you see a pattern? Initially a few dozen compounds would find a product but R4263 (fentanyl) and R33800 (sufentanil) are chemically quite close... but someone made THOUSANDS of compounds to find 1 lead that led to a product.

I think Janssen insisted on a systematic search because the discovery of dextromoramide (R875) is an 'island of activity' i.e. even very closely related compounds had little or no activity. I don't know if his team used rational design, but to me it represents one of the most impressive discoveries ever.

 

[Fertile]

I note that some time ago sekio mentioned embutamide (the most dangerous opioid known to man). Now I have seen that crazy opioid the Swiss invented in my head and so placed them here for people to compare and contrast.

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ibb.co

Who knows how safe the Snadoz compound is?

 

[Delmonte421]

what makes it so dangerous? and man are the Swiss fucking amazing chemists lol

 

[Fertile]

Respiratory depression and ventricular arrhythmia. It's very novel but further reading suggests it's action may be significantly different.

In EVERY case I know, that protected -OCH3 on the aromatic make it a prodrug. It it were an -OH then generally potency is vastly increased. So MAYBE it's possible to make a safe analogue... but animal trials absolutely required. If I don't see a TI of 50+ then forget it.

 

[Delmonte421]

I gotta say, as a fellow chemist, your a smart mf and have such a strong understanding of med chem it boggles me, im young so ill end with that. I don't have the experience you have but I do learn something from you every time I read your explanations of scaffolding etc

 

[Fertile]

Wait - who said I understood this? It's a mystery to me as well! WHY it's so cardiotoxic is absolutely the first thing to discover. I will do so by comparing to similar compounds that selectively act on the heart and work forward. But you know what it's like... it could be weeks or months to find a scaffold that if safer... if their is one to be found.

But believe me, the fact that this stuff is not complex and apparently potent means I CAN see it being used as an active cut. Some people are sociopaths or evil or something. I posted so if an opioid RC turns up that looks ANYTHING like that - people will not touch it.

I have to say that use of a diethyl has to be the simplest way EVER to make the benzylic carbon quaternary.... but no, it's poison.

 

[Delmonte421]

Wait - who said I understood this? It's a mystery to me as well! WHY it's so cardiotoxic is absolutely the first thing to discover. I will do so by comparing to similar compounds that selectively act on the heart and work forward. But you know what it's like... it could be weeks or months to find a scaffold that if safer... if their is one to be found.

But believe me, the fact that this stuff is not complex and apparently potent means I CAN see it being used as an active cut. Some people are sociopaths or evil or something. I posted so if an opioid RC turns up that looks ANYTHING like that - people will not touch it.

I have to say that use of a diethyl has to be the simplest way EVER to make the benzylic carbon quaternary.... but no, it's poison.

like I said your a true blue lighter and you might save a couple lives from what your doing..... CHEERS I got a beer here for ya

 

[AlsoTapered]

3-[2-[2-(Furan-2-yl)ethyl]-2-azabicyclo[3.2.1]octan-5-yl]phenol

3-[2-[2-(Furan-2-yl)ethyl]-2-azabicyclo[3.2.1]octan-5-yl]phenol | C19H23NO2 | CID 20364023 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

Forget patents. Draw what you THINK will be an opioid (based on conformation and 'the morphine rule') and use PubChem to FIND the patent. So, a whole new class and very likely a good lead to others. The ethoheptazines will suggest where to place methyl side-groups onto the cycloseptane ring.

 

[paracelsius]

Try this: Azabyclanes Japanese developed that one (Chinese too, well I mean from Japanese studies)

Anazocine: it is about 1xM, the N-phenethyl 5xM, the meta-hydroxy-N-methyl ca 500xM, the m-hydroxy-N-phenethyl 1200xM. wait! the TI of this later compound is actually above 1000 in rabbits. Just pure Mu, no kappa or delta. Doesnt have any respiratoty depression (IN RABBITS!!) at 1000xanalgesic doses. straighforward two step synth from dirt cheap azabyclanone+ no need worry about enantiomers separation (it is achiral!)! the parent compound is kind of weird tho: it is actually a stimulant AND opioid in rhesus monkey....would post refs when time permitted

edit: the wiki page is totally wrong.oh btw I abhor animal testing!

 

[AlsoTapered]

I did spot that. I wondered about duration because O-demethylation would give -OH which would instantly be rearranged.

So it shows perfect relative position of aryl to O lone-pairs to N-lone pair.

WELL WORTH placing in a training set. A bit of a pig to make, I guess, what with it being a teratogen.

Shows that an 8 membered ring can be active. Dezocine likewise has an 8-membered ring.

I guessed it would be a stimulant, so reference on opioid activity appreciated.

 

[AlsoTapered]

1-(4-Ethylsulfonyl-4,4-diphenylbutan-2-yl)piperidine

1-(4-Ethylsulfonyl-4,4-diphenylbutan-2-yl)piperidine | C23H31NO2S | CID 16206925 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

So in general, an ethylsulfonate is a bioisostere of an ethyl ketone in opioids.

 

[AlsoTapered]

Try this: Azabyclanes Japanese developed that one (Chinese too, well I mean from Japanese studies)

Anazocine: it is about 1xM, the N-phenethyl 5xM, the meta-hydroxy-N-methyl ca 500xM, the m-hydroxy-N-phenethyl 1200xM. wait! the TI of this later compound is actually above 1000 in rabbits. Just pure Mu, no kappa or delta. Doesnt have any respiratoty depression (IN RABBITS!!) at 1000xanalgesic doses. straighforward two step synth from dirt cheap azabyclanone+ no need worry about enantiomers separation (it is achiral!)! the parent compound is kind of weird tho: it is actually a stimulant AND opioid in rhesus monkey....would post refs when time permitted

edit: the wiki page is totally wrong.oh btw I abhor animal testing!

(1R,5S)-9-methoxy-9-phenyl-3-(2-phenylethyl)-3-azabicyclo[3.3.1]nonane

(1R,5S)-9-methoxy-9-phenyl-3-(2-phenylethyl)-3-azabicyclo[3.3.1]nonane | C23H29NO | CID 21151698 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

 

[paracelsius]

I did spot that. I wondered about duration because O-demethylation would give -OH which would instantly be rearranged.

So it shows perfect relative position of aryl to O lone-pairs to N-lone pair.

WELL WORTH placing in a training set. A bit of a pig to make, I guess, what with it being a teratogen.

Shows that an 8 membered ring can be active. Dezocine likewise has an 8-membered ring.

I guessed it would be a stimulant, so reference on opioid activity appreciated.

what makes you think O-demethylation? if anything that methoxy on a tertiary carbon is pretty well shielded from demethylases. I would suspect N-demethylation but who knows unless it is studied specifically hard to predict metabolism.

that teratogen ref on wiki is utter bullshit..no data no ref to data no nothing just a list of chem presumed teratogen.. I have yet to see data on those compounds.. pure bs imo.. I mean the list includes sodium chloride as teratogen..ffs NaCl aka table salt! the second most abundant chemical after water in living cells! I wouldnt take that seriously.

Duration of parent compound 3-4h. the meta-hyrdoxy has faster onset but shorter duration. the one you post is about 5xM its meta-hydroxy actually 1600xM!! not 1200 as I mentioned with longer duration. I mean so potent those guys thought it irreversible (cant wash it bound to MOR even with ohmefentanyl but it is not (just super potent). has pretty wide TI tho (cf the chinese paper compound P-7521). paper in chinese/english abstract! I would go for the N-methyl-meta-hydroxy: 5M, fast onset(~1-2min) but less than 3h duration , not bad. synthe of those is rather straigforward (2-steps cheap precursor..cf the original JP ref)..

The "pig to make" is dezocine that you mentioned. Now this compound is the biggest selling opioid in China (40% market share), the second biggest market after US, huge! Now this one is a pig to make, multistep complicated sequence, hard to scale + you end up throwing away half the final product (the inanctive enantiomer). I've seen couple of recent patents for said synthesis. If you can come up with cheaper, easier scalable synth method, you'd be a billionaire! believe (the demand for this one in China is thru the roof but limited supply bc it is hard to make!.. (cf Abu Grabia review of Dezocine in Chemical Neuroscience..)


P-7521--a new irreversible opioid ligand https://pubmed.ncbi.nlm.nih.gov/2558497/

Effects of the long-acting analgesics 3-(beta-phenylethyl)-9 beta-methoxy-9 alpha-(m-hydroxyphenyl)-3-azabicycles [3,3,1]-nonane (P-7521) on opiate receptor binding in vitro] https://pubmed.ncbi.nlm.nih.gov/2855686/

Kobayashi S, Hasegawa K, Oshima T, Takagi H (September 1970). "The pharmacology of azabicyclane, a new analgesic agent". Toxicology and Applied Pharmacology. 17 (2): 344–54. doi:10.1016/0041-008X(70)90191-2. PMID 5528556.
Froimowitz, Mark; Salva, P; Hite, G. J; Gianutsos, G; Suzdak, P; Heyman, R (1984). "Conformational properties of α- and β-azabicyclane opiates. The effect of conformation on pharmacological activity". Journal of Computational Chemistry. 5 (4): 291–298. doi:10.1002/jcc.540050403. S2CID 97334125.
Kobayashi S, Hasegawa K, Oshima T, Takagi H (September 1970). "The pharmacology of azabicyclane, a new analgesic agent". Toxicol. Appl. Pharmacol. 17 (2): 344–54. doi:10.1016/0041-008X(70)90191-2. PMID 5528556.

oh btw did you change your pseudo "Fertile" or am I talking to another person... not sure but Fertilidine would be nice for the up most opioid expert on BL !

Good'day All BLighters. Stay Safe Out There

 

[AlsoTapered]

Some examples have a m-MeO and as you know, USUALLY it's a m-OH (or bioisostere) that engenders affinity. BUT it's also a requirement for antagonist activity. Find an antagonist without it.

But there are so many of these theoretically super-potent ligands. The problem is the cost and complexity makes them impractical.

Dezocine MAY be just 2 steps. Almost anything you care to name is just 1 or 2 steps. But from where and how costly and available are the precursors?

At such scales, you can be sure they make it from much simpler precursors. But dezocine is popular because it's a mixed agonist-antagonist so for clinical purposes, it's less likely to produce addiction. To be honest, the source I usually use doesn't deal with China's internal usage but it would appear that it has to be stored as a solution and injected. Not that potent either, so by MASS it would score much higher than, say, sufentanil.

Let's face it, AP-237 was previously the majority of all opioids prescribed in China. It doesn't mean it's any good. Long, long ago someone sent us a sample and we didn't bother. U-47700 is 1 step from cheap, readily available chemicals.

I'm glad PubChem is catching on. One can simply sit there and using a substructure or similarity, find all of the references on even the most obscure compounds. Not quite as good as Reaxys, but still amazing for free.

 

[AlsoTapered]

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ibb.co

(S) phenoperidine is around x120 M. I cannot understand why Mexicans don't make it. No harder than MPPP to make and if you introduce a 3-(R) on the piperidine, it's x480 M AND the precursors are not watched.

Hey just for fun - what's the most potent opioid one cam make in 1 step from unwatched precursors? I have x20. BUT to be clear, it has to be in Sigma or such.

 

[Everlasting Reign]

It is revealed in the old medical literature that phenoperidine has profound respiratory depressant properties and was therefore used chiefly for surgical procedures under mechanical ventilation or at the least in easy reach of an antagonist. That and its high potency leads me to believe that it would be hecka risky to use recreationally, maybe even moreso than fentanyl.

 

[AlsoTapered]

It is revealed in the old medical literature that phenoperidine has profound respiratory depressant properties and was therefore used chiefly for surgical procedures under mechanical ventilation or at the least in easy reach of an antagonist. That and its high potency leads me to believe that it would be hecka risky to use recreationally, maybe even moreso than fentanyl.

Indeed - at the doses required for surgical anesthesia. It was replaced by a mixture of fentanyl and droperidol.


Title: STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XXII: PHENOPERIDINE AND FENTANYL, ALONE AND IN COMBINATION WITH DROPERIDOL
Series: BJA British Journal of Anaesthesia 1970-dec vol. 42 iss. 12
Author(s): MORRISON, J. D.

Table IV on page 1122 suggests that their toxic liability to be similar.

And when yo look at the doses involved.... they seem rather... heroic. 0.2mg of fentanyl vs. 2mg of phenoperidine? So it's not quite comparing their mu affinity alone but other actions of the 2 drugs. When that chain is 2-long, it's purely an opioid. When it's 4 long, it's purely a neuroleptic and so 3 will display some median activity.

I t's worth looking at PubMed to look at the related compounds. Someone reversed the ester (although this actually results in a slight reduction of potency in the case of phenoperidine) BUT then allowed them to produce the 3-methyl and 3-allyl derivatives... and a p-F derivative!

I don't THINK anyone tried to replace the 3-hydroxy-3-phenyl propyl moiety with a 3-hydroxy-3-(2-thineyl) propyl (as per fentanyl -> thiofentanyl) or indeed do much with the scaffold. I think it's because Janssen's patent on phenoperidine was about to run out so fentanyl (in patent) was preferred.

I'm not saying phenoperidine is safe, but it's sedating properties are likely to make people nod and let's be honest, it's not like the people making such drugs care much about the end user.

If they DID but insisted on a fentanyl derivative, sufentanil is pretty impressive. x10 more potent than fentanyl and with a TI of 16700! Weight for weight LESS toxic than fentanyl by a long way.

Placing an (S) -OH onto the same carbon as the pendent aromatic is connected to seems to significantly increase activity in a lot of otherwise unrelated opioids. It's only known (to most) in fentanyl & phenoperidine but in every opioid bearing an N-ehtylaryl moiety, that (S) -OH always seems to make a BIG difference.

But thank you for looking! I do appreciate that people are reading this stuff. My new method of searching for opioids is to find a scaffold and use PubMed to find 'similar' which is how I was able to find crazy things....

 

[Delmonte421]

I cannot understand why Mexicans don't make it. No harder than MPPP

In 1976, a 23-year-old graduate student in chemistry named Barry Kidston was searching for a way to make a legal recreational drug. Having read the paper by Ziering and Lee, he deduced that he could make a drug with pethidine's effects without its legal restrictions, since desmethylprodine is a different molecule and had never been addressed by law. Kidston successfully synthesized and used desmethylprodine for several months, after which he suddenly came down with the symptoms of Parkinson's disease and was hospitalized. Physicians were perplexed, since Parkinson's disease would be a great rarity in someone so young, but L-dopa, the standard drug for Parkinson's, relieved his symptoms. L-dopa is a precursor for dopamine, the neurotransmitter whose lack produces Parkinson's symptoms. It was later found that his development of Parkinson's was due to a common impurity in the synthesis of MPPP called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that specifically targets dopamine producing neurons.[4][5]

In the United States, MPPP is now in Schedule I of the Controlled Substances Act with a zero aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.87 for the hydrochloride.[6] It is listed under the Single Convention on Narcotic Drugs and is controlled in most countries in the same fashion as is morphine. Source

 

[AlsoTapered]

NOVA; Case of the Frozen Addict, The

openvault.wgbh.org

Yeah, an episode of Horizon (BBC) covered it in 1987. Some US documentary makers modified the script a little and of course a US voice actor was used.

Dr. ALBERT ZIERING spent several years at Hoffman-LaRoche working on the QSAR of the phenylpiperidine class of opioid. He stuck to just the N-methyl derivatives but did just about everything else possible. Of course, since pethidine (demerol) is still QUITE toxic, he worked in a fume-cupboard. I think he died in 2015 i.e. in his late 90s.

https://pubs.acs.org/doi/abs/10.1021/jo01170a022

 

[AlsoTapered]

Try this: Azabyclanes Japanese developed that one (Chinese too, well I mean from Japanese studies)

Anazocine: it is about 1xM, the N-phenethyl 5xM, the meta-hydroxy-N-methyl ca 500xM, the m-hydroxy-N-phenethyl 1200xM. wait! the TI of this later compound is actually above 1000 in rabbits. Just pure Mu, no kappa or delta. Doesnt have any respiratoty depression (IN RABBITS!!) at 1000xanalgesic doses. straighforward two step synth from dirt cheap azabyclanone+ no need worry about enantiomers separation (it is achiral!)! the parent compound is kind of weird tho: it is actually a stimulant AND opioid in rhesus monkey....would post refs when time permitted

edit: the wiki page is totally wrong.oh btw I abhor animal testing!

Library Genesis

libgen.rocks

Library Genesis

libgen.rocks

Hotlink to papers.

I also note that the N-phenylethyl derivative is also known BUT I suspect that the LogP is too high. Now, IF that turned out to be the issue, then the 2-hydroxy-2-phenylethyl, 2-(2-thienyl)ethyl) or even the 2-hydroxy-2-(2-thienyl)ethyl MIGHT solve the problem. If so, I would fully expect them to have a potency in the range of x35000-x45000M (conformation permitting).

But is it a facile target? I suspect not. So fascinating and well worth knowing for when one is seeking to design a training set, but I know of much simpler compounds (1 step synthesis) that proved not to be practical because the precursors were too costly, even if their potency was some x500 M.