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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