Meptazinol, novel unscheduled opioid

Looks like a compound that's been marketed in Europe but is still unscheduled in the U.S.



Has mixed agonist/antagonist action similar to buprenorphine.

Very mild partial agonist used for patients who can't take codeine. No longer used in the UK. Not much good for anything.

FYI: It was marketed by Schering, under the name Meptid and was available in the form of 200 mg tablets and 100mg/ml injection liquid.

Patent literature on this molecule is fairly recent.

Structure drawn with ChemDraw Professional 17.

Jack

haribo1 said:

Very mild partial agonist used for patients who can't take codeine. No longer used in the UK. Not much good for anything.

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weaker than codeine eh... sounds pretty useless. You could get more effect from the dried up old poppy seeds at walmart.

Interesting. A phenolic opioid whose (R) enantiomer is a partial agonist at the μ receptors while the (S) has affinity for the muscarinic receptors. If the ethyl is replaced with a methyl, it becomes an antagonist while lengthening it to an n-propyl makes it an agonist. Picenadol is an interesting overlay to anyone using Chemoffice. It throws up the possibility that adding a 3-methyl group to ketobemidone DOES make it stronger but while the (S)-trans isomer is a full agonist but the (R)-trans isomer is a full antagonist. So that would be an interesting path to go through. Many years ago I posted a patent for the N-2-furan-2-ylmethyl analogues that were some x15 the parent for analgesia (likely KOR involved). It think that a lone-pair two carbons from the basic amine infers more potency. It is also interesting that the -OH can be replaced with an -C(O)NH2 for longer action.

In each case, the complexity and uncertainty means that you could spend several weeks of translating and reading just to arrive at the point of deciding it's too much work.

I've had it (UK) didn't know it had been discontinued, when was that?

I found it disgusting stuff. Interesting pharmacologically, in that it is a selective agonist for the MOR1 isoform of the MOR receptor, partial agonist, I'd say stronger than codeine but I couldn't tolerate it. It did a real number on my guts and left me doubled over in pain. Thinking this might be due (it happened even in opioid withdrawal so I think perhaps inherent to the properties of the drug itself, whereas a partial agonist would have made me feel better by some at least in full WD), but thinking it may be due to the bare phenolic moiety, the propionyl and benzoyl phenolic esters were tried, which, well to sum it up, only one of the two got tried, forget which as this was nearly 6 years ago maybe 7. And both the rest of it, and the other ester were chucked out.

They used it as a stronger than codeine alternative here, for those who couldn't take morphia or its relatives and were nontolerant and so fent etc. couldn't be used. My former housemate was scripted it and I seized all she had when i kicked her to the curb to experiment on and with. Nothing good ever came of it and all projects were scrapped. (if anyone was wondering about the housemate, she had it coming, she was a borderline PD bitch from fucking hell, who stole and hoarded my meds to try and make me go into WD, and then try to control me through controlling access to her own meds. Eventually she made at least one, probably two and possibly three attempts on my life, after which of course I kicked her ass out with nothing but the clothes on her back and an asthma inhaler thrown at her, after she tried outright, to gut me with a katana, only to find herself facing a swordsman more skilled than she, disarmed and beaten senseless. Had stolen money from my family, made false rape claims against not me, but two or three other people just to get an advantage over them and get things out of them. Real dirtbag, so as I saw it any of her possessions, once I had kicked her out, were mine for the taking as I saw fit, for she had no rights as a person, for a person she was and is not)

Bugger meptazinol and its esters though. Not worth the reagents it took to make them or the effort taken to recrystallize the stuff.
Longer action? trust me, you don't want longer acting meptazinol. It might well leave you doubled over in the foetal position begging for it to stop.

The BNF listed it as a codeine alternative. 200 & 400mg tablets, if I recall correctly. I bet optical resolution would be interesting. I came close to strangling a lazy frog for refusing to racemize ethylphenidate so only the trans isomers (read active isomers) were left. When someone is too lazy to do that, you know that a rug on Valium would do a better job...

Strangling a lazy frog? I am unfamiliar with the idiom.

It is/was a weakish alternative to weak-very modest opioids of more traditional types. It might well not substitute well in an opioid naive person or non-dependent patient, as its MOR1 isoform selective.

As for the esters, one of them was utter shit, the other one that was made, ended up going down the toilet, although whichever ester was tried did seem to resolve the vicious GI tract-ripper effect of the parent drug. But the one that went down the loo, lets just say that it did not first pass through the digestive system of the chemist who made it. And he considers both to have been rather a waste of two acyl halides and the triethylenetetramine used to absorb the released hydrogen chloride.

Meptazinol really isn't worth fucking with, its weak, it isn't a broad-spectrum MOR full agonist and it can really do a number on your guts. Esterification can help ameliorate the last, but its still fucking shite. And as for its being unscheduled in the US, probably because its bollocks.

But..strangling a lazy frog? what the hell's teeth does that mean.

Sorry, anger at lazy chemists. If you replace the ethyl with a propiophenone, you have an overlay for ketobemidone. As I have mentioned, I think a 3-methyl on ketobemidose DOES make the trans isomers much more potent but one is a full agonist, the other an antagonist, that is why research dried up on that class. Replacing the N-methyl with an N-2-furanylmethyl, the product is x15 BUT it may be delta (not a disaster) or kappa (DISASTER) mediated. I noted that 2-tetrahydrofuranylmethyl (chiral centre) derivatives of morphine show one agonist and one antagonst. Without that chiral centre, the question is if minimum-energy is in agonist or antagonist conformation.

Interesting regarding ketobemidone. Depends on how practical it would be to separate the isomers of the propiophenone derivative of meptazinol you suggested there, or else separate adduct derivatives or N-protected compounds amenable to mild deprotecting conditions of separation of cis/trans isomers of the meptazinol compound. Might be one of those things that never ends up being looked at though, because I don't really want to wade through a ton of garbage and then accidentally hit myself with a potent opioid antagonist (I'm a chronic pain patient and on oxy and morphine, hopefully in the next few days memantine also as an adjunct, although that is by far away my main reason for that one, its just the excuse for off-label use that me and my GP can hope to swing most effectively), antagonists would NOT be pretty for me. Or anybody within projectile puke range either for that matter.

As for a DOR agonist, could be a problem, might not be. Would depend on subtype affinity/efficacy as well as agonist action at MORs. Some (always forget if its DOR1 or DOR2) but not all delta opioid agonists are convulsant in excess. I haven't much direct experience at all with DOR agonists, and unless the results of a chlorination of morphine sulfate using SOCL2 was something by way of a strychnine-sensitive glycine receptor antagonist, then that peculiar psychostimulant compound in doses that did not feel in any way threatening of convulsive action is probably the only reasonably selective DOR agonist I've tried, and that is based on personal bioassay trials rather than receptor binding and displacement probes.

- 1-[1-(furan-2-ylmethyl)-4-(3-hydroxyphenyl)piperidin-4-yl]propan-1-one has been patented so the N-methyl to --->N-furan-2-ylmethyl substitution increases potency x15.
- Picenadol confirms that the (3R,4R) aka R-trans enantiomer. Prodine is a full agonist while the (3S,4S) is an antagonist (not just a silent agonist).
- The 3-methyl derivatives of both pethidine and it's reversed ester are an order of magnitude more potent than the patent compound.
- The 3-methyl derivatives of bioisosteres of pethidine are an order of magnitude more potent than the parent compound.
- The bioisosteres of ketobemidone are equipotent (sulfonyl).
- The bioisosteres of allylprodine are equipotent (sulfonyl).

What has never been researched is the 3-allyl homologues of allylprodine. I am going to suggest they are equipotent.

Got to admit, given that a mixed cis-trans pair is going to contain both an inverse agonist and a (potentially) full agonist, without enantioselective synthetic route, I'd probably (personally) rather avoid synthesis attempts. But not due to laziness, rather, to potential for a screwup in purification, given that as a chronic pain patient, a MOR inverse agonist is NOT something I want anything to do with.

Do meptazinol analogs retain their MOR1 isoform selectivity, in the case of any of these full agonists? because that could forseeably result in a functionally (partially) antagonistic profile, given that MOR2 and MOR3 subtypes would remain untouched, and as a result there would be only partial coverage with respect to E.g morphine. Not sure quite what effect that would have on a subject dependent on a broader-spectrum full agonist, but it probably wouldn't be a good one.

The research into meptazinol is all really old. I don't think mu subtypes were understood when the stuff was designed but I seem to recall a little later work and it was a partial agonist at both (before mu3 was accepted - so that is an unknown).

The resolution isn't actually as difficult as it appears. Either the minimum-energy conformation or a near-minimum conformation lends itself to chiral acids 'known to those skilled in the art' as every patent everywhere ever when dealing with an unpatented aspect. I might add that the 3,3-dimethyl derivative of pethidine is known. It popped up on Reaxys when I spotted dimethylaminopivalophenone in the Annual Report in Medicinal Chemistry (all on the Eunoia disc). That a single oxygen species (also seen in AH-7921 & U-47700) confirs activity and that the position of that oxygen, be it ketone, hydroxyl, ether or sulfone can be classed as a hydrogen-bond acceptor is interesting.
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Limpet_Chicken said:

I haven't much direct experience at all with DOR agonists, and unless the results of a chlorination of morphine sulfate using SOCL2 was something by way of a strychnine-sensitive glycine receptor antagonist, then that peculiar psychostimulant compound in doses that did not feel in any way threatening of convulsive action is probably the only reasonably selective DOR agonist I've tried, and that is based on personal bioassay trials rather than receptor binding and displacement probes.

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Although I can't quickly find any affinity values for halomorphides as I'm running short on time, and there may not be any, based on known affinities of different 4,5-epoxymorphinans and plain morphinans there is definitely no reason to suspect that chloromorphide, regardless of stereochemistry at C6, would be a selective delta agonist to any degree. Simple direct morphine analogues are basically mu and kappa ligands with generally less affinity at kappa receptors and much much less affinity at delta receptors. Unless you put a very specific bulky moiety on the C ring like in naltrindole or naltriben, you don't observe selective delta agonists in the morphinan family of opioids. Finding a non-peptide selective delta ligand like naltrindole was actually a breakthrough, I would say, I can't think of any other delta selective ligands other than peptides like DADLE or DPDPE. Even plain morphinans which are fairly unselective among opioids structurally based on the morphinan core and aside from high affinity to mu and kappa receptors have a relatively high affinity to delta receptors, like levorphanol, bind preferentially to mu and kappa receptors.

Heh its just a case of once bitten, twice shy. I've not forgot what meptazinol did to me in over five fucking years. Goddamn...I'd sooner take a 'line' of Na metal up the nose than take anything that even LOOKS like that fucker ever again, and I KNOW what that is like (long story short...electrolytic cell, funky angle, argon tank ran dry, bang, hello nasal crater for a while and a lot of rather profane language used in a short time)

Direct similarities CAN exist in morphine analogs. In certain circumstances. Right now I'm about 10 minutes from refilling my own morphine/oxy tank so forgive me for not citing the literature just yet, But apparently, whilst presumably not totally selective, IIRC part of the incomplete crosstolerance in morphine-dependent rats, at least, alternative splicing isoforms aside of MOR, of which there are more than we both have had hot dinners from the way things were last time I read up, both H and 6-monoacetylmorphine undergo a shift in binding, from MOR/DOR, with each being subtype selective in the degree of its DOR agonism. Something I've long found fascinating, given the widely touted story that H etc are just fast-delivery systems.

What I'd not give to know what the case is for the mono and dipropionyl esters....since I never did run into H a great deal, and the only connect I had is dead...and I'd not waste the reagents to make it myself when the dipropionyl ester is available as a target.

What about mitragynine pseudindoxyl? although not sure if its selective.

Adder - I spotted an interesting thing in Chemoffice. As you know, the etonitazene derivative with the benzylic amide (listed as x200 compared to x60 for plain etonitazene). Well the nitrogen of the (S) isomer overlays the piperidine nitrogen of MCOPPB. I don't know if that detail is common currency but I found it interesting. Of course, I was educated to use the term ORL1, not NOP like the kids today. It has never been tested for NOP affinity but I'm prepared to bet that a hydroxyl would also work.