Thread: Phenylpiperidine Opioids - how low can you go?

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    Phenylpiperidine Opioids - how low can you go? 

    So, we have a chiral carboxamide as a bioisostere of a phenolic group, an ethylsulfonyl group as bioisostere of ethyl ketone and shock - an N-2-furanylbenzyl as bioisostere of the common or garden N-ethylaryl. I have an unknown. Substitution of the piperidine ring is supposed to be verboten for ketobemidones BUT picenadol (LY-97435) suggests the reason why such substitution failed was simply because like many phenolic opioids, they can be agonists and/or antagonists. I dare not believe that swapping the methyl for an allyl would engender a serious increase in potency BUT it does raise the issue of what has been left untested. When the side-chain bares no oxygen, the chain-length is important. A methyl is an antagonist, an ethyl is a partial agonist (see meptazinol) while (S)-picenadol is an agonist.

    It has nothing special to make it a clandestine target but as a series including the 2,5-dimethyl as well as various 3-n-alkyls and N-benzylaryl groups (thiophene, thiazole, oxazole & isoazole for example) WOULD be of tremendous value as a training set. MANY 5 & 6 membered aromatic rings have been placed onto the anilidopiperidine scaffold and many times more on the dual mu/delta ligands that have gone nowhere but the example I give is one of around x20 morphine based on the (English) patents.

    Going even simpler, dimethylaminopivalophenone overlays 3,3-dimethylpethidine BUT the position of the O is the same as one of the Os in allylprodine so what activity would people predict for dimethylamino-3-allyl-3-methyl-heptephenone (suppose it's about as accurate as the original!). If the allyl works I predict that replacing the N-methyl for an N-allyl in U-47700 will have pronounced effects.
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    Neuroscience and Pharmacology Discussion
    sekio's Avatar
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    That almost looks like carfentanil.

    Are carboxamides really chiral under those conditions though? Biphenyl-3-carboxamide is achiral so shouldn't it be achiral on the (sterically uncrowded) pethidine skeleton?
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    It is chiral according to Mark P. Wentland and co-workers in Cogswell Laboratory at Rensselaer Polytechnic Institute. There is a raft of patents and papers on the benzomorphan scaffold but the amide is chiral... That is a VERY interesting piece of information. I do not believe this is widely known. I'm purely interested in the ways to improve acute safety. I am sickened by the endless tide of phenylpropanamide opioids wreaking havoc all over the world. In the 1950s it was noted that substitution of the N-methyl of levorphanol (Levo-Dromoral) with a 2-arylethyl had an ED50 some 1/60th of the parent, the LD50 was HIGHER (by MW specifically) and a chiral β-hydroxy reduces that to 1/240 (by MW again) so already the TI is 2 orders of magnitude larger. It is possible to improve delta & keppa-3 affinity to reduced the ED50 by another couple of orders of magnitude and the LD50 is once again increased by the same ratio.

    So you can produce something in the range of carfentanil with an LD50 in the range of codeine. It isn't that it needs a long, complex and/or expensive synthetic pathway. It's ignorance, laziness and to produce a crack-like (ab)use pattern. If something has a T1/2 of 4-6 hours BID, not even TID is all that is needed to stop people being sick, you don't sell many units. When I see reports on fentanyl caps at $2 each, the low price many units model is in place. The Russians call tropicamide '8 monther' for a reason and I presume fentanyl has similar names.

    I cannot quite understand the mindset of someone who is happy to grow rich on the misery of others. Something much, much better than diamorphine would surely not come to the attention of law enforcement is nobody is dying or carrying out desperate criminal acts to constantly feed the needle. Sublingual tablets like the very old UK diamorphine 'jacks' and with appropriate livery, you could reduce the harm hugely. The bar is quite low - alcohol and nicotine are deadly. We can and should be doing better for people.

    For joint mu/kappa-3 look at the etonitazene derivatives with a carboxamide on the methylene spacer. for joint mu/delta look at allylprodine, cinnamyloxycodeinone & etorphone. Run a training set through CHARMM (with selective k-3, selective delta & selective mu). I used a set of 96 so the thing chugged away for a good couple of weeks but who knew and alkene is an important moiety? I'm dubious of modern in-silico models but old fashioned 3D QSAR works if you train them correctly. I don't think I'm smarter than anyone else but I always try to be informed. Yes, I am often wrong, but it is the answer that is important, not how the answer was arrived at (as long as it's legal and moral).
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    Frankly, My Dear...

    Last edited by Dresden; 02-05-2018 at 15:41.
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    Esters don't substitute for ketones. Sulfonates & phosphine oxides do. Reducing the ketone moiety of ketobemidone and esterification of that would be interesting.
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    The Proof Is In The Pudding.
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    Quote Originally Posted by Dresden View Post
    The Proof Is In The Pudding.
    Well the ethanesulfonate works. The phenol-->carboxamine i'm prepared to bet will work but the N-(2-furyl)benzyl may have unselective kappa activity. They were 15x more potent in animal models but who knows if it's nice. Adding a 3-methyl works as long as you can resolve the trans-pair. One is an agonist, the other an antagonist (which is why early research discounted it) so (S,S) 3-methyl ketobemidone is an order of magnitude more potent.
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    I love your posts, but can you draw more pictures?
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    Note (3R,4R) isomer is the agonist, while (3S,4S) is antagonist.

    The reason why substitution of the piperidine ring of ketobemidone didn't seem to work was because phenol-bearing opioids can be antagonists. From the extant data we can infer that 1-[(3R,4S)-4-(3-hydroxyphenyl)-1,3-dimethylpiperidin-4-yl]propan-1-one will be around a magnitude more potent than it's parent, ketobemidone. Phenol bearing phenylpiperidines do not follow the N-substitution patterns of the non-phenolic ones. A british patent listed 1-[1-(furan-2-ylmethyl)-4-(3-hydroxyphenyl)piperidin-4-yl]propan-1-one ketobemidone derivative as some x15 more potent than the parent. N-moieties with a nitrogen 2 methylenes from the piperidine N means we can infer it's the lone-pair that is critical. Put it all together and 1-[(3R,4S)-1-(furan-2-ylmethyl)-4-(3-hydroxyphenyl)-3-methylpiperidin-4-yl]propan-1-one is going to have 2 extra moieties that improve affinity.

    Not possible to say if it will be euphoric (kappa 1/2 agonism an issue) but from extensive studies and my own work using CHARMM, I would expect it to be some 100-150 x the parent. Of course, CsA laws apply so swapping ketone for an ethylsulfonyl (tested on both phenolic & non-phenolic phenylpiperidines and is equipotent so 3-[(3S,4S)-4-(ethylsulfonyl)-1-(furan-2-ylmethyl)-3-methylpiperidin-4-yl]phenol shoult work and swapping phenol for carboxamide leads to the compound I drew.
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    What do you think of this? It's loosely based on picenadol.

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    Looks like if fentanyl and demerol had a baby. But ignore me, I'm not qualified to make such statements.
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    Well it isn't phenolic... it will metabolize to a phenolic compound and non-phenolic bemidones aren't that active BUT and alpha methyl will harden the stuff. Swap benzene for 2-furan and dump ring-substitution. I reckon it would be active. Not safe, not good, not something I would try but active.... but something that kills you is active as well :-D
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