Most pleasurable opioid based on pharmacology?

[Nas47]

Are you old enough to remember Dextromoramide, Dipipanone and such?

Neither were THAT strong (former x3M, latter x2M) but it was the RUSH, plateau and cruise back to zero that were all amazing. I haven't tried the mixtures you have but I do appreciate that all of the wonderful effects were mediated by just 1 compound.

As I said, I am confident that swapping the cycloppentane moiety of dextromoramide being swapped a pyrrolidine ring will work - it will be more lipophilic and so it's potency should be slightly higher.... but although based on a lot of QSAR study, nobody can confirm that. Diconal (dipipanone + cyclizine was amazing and maybe a large part was because Diconal tablets were 10mg dextromoramide + 30mg cyclizine so IV use gave a rugh generally agreed to be the best of all drugs ever. I mean, it was BANNED because people sought it out for that effect.

In short, what one wants is a potent opioid with fast onset mixed with a first generation antihistamine (all of which increase effects of opioids).. From what I know, the antihistamines make the opioid cross the BBB very fast and so the initial concentration of the drug is within the CNS and it's distribution that moves it equally throughout the body.

ALL of these compounds were either administered IV or snorted. The volume of distribution means that it STAYS in the fatty tissue of the brain. Oh, and dipipanone actively (like all 3,3-diphenylheptanone) opioids act the same way.

I BET that a lot of the 3,3-diphenylheptanone opioids that would do the same. I mean drugs that were not about when cyclizine was developed.

I mean, the N-pyrrolidine homologue of dipipanone is MORE potent (and legal in many places), the pyrrolidine homologue of dextromoramide homologue of dextromoramide is legal and as for methadone, well, from R-4065 downwards - durations of 72 hours are USED. There are analogues with a duration of over 7 days!!!!

I remember these old analogus,but never tried.Heard a lot of stories of old palfium use-80:years,still in commies times.

 

[Feretile]

I have to admit that a pyrrolidine can adopt 2 conformers for it's minimum energy conformation and although their are not chiral, steric bulk may prevent the C-N bond from rotating. I am still quite sure that the pyrrole homologue would be almost identical to dextromoramide. In fact, duration might be slightly longer.

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The pyrrole ring will be planer whereas the pyrrolidine ring has bond angles of about 109° so it isn't planer. Now, I admit that this is a total guess, but I do not think that this makes much difference to affinity or activity. As far as I know, Janssen didn't try placing aromatics on amide, ketone or ester moieties (but maybe someone else knows better). There are quite a few cases where he COULD, but he didn't.

I think that the reason that a 5-membered ring is the only homologue that is highly active is that it's space-filling (in conjunction with that alpha methyl) rotates one of the benzene rings so that it fits the receptor, affinity is increased a great deal. I mean, the piperidine homologue is almost inactive. Of course, he never tried 2,3-dimethyl cyclopropane or 2,3-cyclobutane homologues.. Imagine - lots of fun with optical isomers!

But it is my experience that when medicinal chemists discover a REALLY active homologue, they tend to take the afternoon off. I know this sounds glib but Dan (Lednicer) never made the p-Me homologue of BDPC and when I asked 'why?' he just said 'in all of the excitement, we forgot.'. I mean, I LOVE Dan for that, he was such a human person.

I guess the other (in)famous example of space-filling is when the diethylamide moiety of LSD can be replaced by an (S,S)2,4-dimethylazetidine or a mono sec-butylamide. Hoffman found this example that was magnitudes more potent than closely related compounds and just stopped. I guess from a medicine chemists point of view, they HAVE an appropriate ligand and their would be no prizes for finding a second one.

For this interested, in the N-benzyl derivatives of the PEA class, the benzene ring fills the space occupied by the diethyl in LSD and the O of the -OH or -OCH overlays the =O of the amide moiety.

I mean, I respect the German guy for thinking outside the box and for proving that an o-hydroxy or o-methoxy benzene acts as a bioisostere to a diethylamide.

I seem to have rambles.... sorry.

 

[purplehaze147]

There's different subunits of opioid receptors, not just the MOR, KOR, and DOR. There's at least 2 subunits for the mu-opioid receptors. I'm not sure if they ever got that detailed with everything