Oxpheneridine opioid in Canada

[paracelsius]

just trying to get my head around that one: why is this opioid specifically excluded from Schedule in Canada.??

Oxpheneridine[1] (Carbamethidine) is a 4-phenylpiperidine derivative that is related to the opioid analgesic drug pethidine (meperidine)....In Canada, Oxpheneridine is specifically excluded from the illegal drugs list on the Controlled Drugs and Substances Act schedules, presumably on the basis of the lack of addictive potential found by the UNODC (wiki)

lack of addictive potential?? hmmm not sure how the UN functionaries come up with that conclusion!!
I mean this compound is a potent mu opioid agonist about 5x morph, ~10x more potent than pethidine. but yet morph, and pretty much all piperidines are classified but not that specific opioid. Technically that means it is perfectly legal in Canada or am i missing something?

 

[polymath]

The Wiki article says that it is too strong irritant to dose in large amounts. I'm not sure what exactly makes it have that effect. It could even bind to the same vanilloid receptors as the tear gas compounds capsaicin and nonivamide.

 

[S.J.B.]

Indeed, oxpheneridine is explicitly unscheduled in Canada, and therefore legal to buy and sell without a licence as long as it is not sold as a food or a drug, etc. The reasoning behind this is based on a UN Bulletin on Narcotics from 1958, where they decided it was unnecessary to put oxpheneridine under international control:

1-(2-Hydroxy-2-phenyl-ethyl)-4-phenylpiperidine-4-carboxylic acid, ethyl ester (oxpheneridine17 )

In its sixth report 18 the Committee decided to defer its opinion with respect to oxpheneridine because the information then available was of a preliminary nature. In subsequent tests it was not possible to administer sufficienty large doses of this drug on account of its insolubility and its extremely irritating properties. In the doses applied significant addiction liability was not demonstrated. Therefore the Committee was of the opinion that at this stage oxpheneridine need not be regarded as an addiction-producing substance with morphine-like effect.

 

[sekio]

wonder what happens if you throw a phosphate onto that hydroxy

 

[paracelsius]

^ Good idea! a prodrug ala psilocybin-psilocin duo.. that would almost certainly solve both the irritation and solubility problems mentioned!

But actually, I don't think it is more irritating than the parent desoxy compound (pheneridine). Which btw is less potent but Scheduled by Canadians!! go figure!

What I suspect might have happened with the UN functionaries though is that if you look at this compound, the obvious synth is to alkylate the nitrogen of normeperidine with phenacyl bromide (alfa-bromo-acetophenone) and then reduce the ketone. Or the chloride is same.. now, phenacyl halide are EXTREMELLY irritating lacrymators chemical used in ...uhhh tear gas! By coppers to harass protesters. (if you have ever been even slightly exposed to it in a lab or in a protest gassing, you'd known what I am talking about!)

My hunch is that uncarefully prepared sample of oxpheneridine that may contain even traces of phenacyl bromide would be VERY irritating!.. but I don't know, just a hunch. Since it doesn't say how it was made or “irritating” to what (eyes, nasal, oral, sc, IV??) to whom? mice, rats, dogs, cats, rabbits, the experimenter??. I just don't believe it is more irritating (or less addictive) than the parent desoxy (pheneraridine) or other phenyl piperidines opioids.

As for the solubility issue, I dont see why it should be less soluble than the parent compound pheneridine (lacking the alfa hydroxy). If anything adding a hydroxy will normally INCREASE, not decrease the water solubility!!! I suspect they were probably dealing with the free base at high pHs.. but who knows?

 

[sekio]

so carbamethidine is a different drug entirely:

also alpha-bromoacetophenone would be reduced just as easily as oxo-oxpheneridine

If anything adding a hydroxy will normally INCREASE, not decrease the water solubility!!!

sometimes it can set up the possibility for hydrogen bonding and hence stabilize the crystal form

 

[polymath]

What I suspect might have happened with the UN functionaries though is that if you look at this compound, the obvious synth is to alkylate the nitrogen of normeperidine with phenacyl bromide (alfa-bromo-acetophenone) and then reduce the ketone. Or the chloride is same.. now, phenacyl halide are EXTREMELLY irritating lacrymators chemical used in ...uhhh tear gas! By coppers to harass protesters. (if you have ever been even slightly exposed to it in a lab or in a protest gassing, you'd known what I am talking about!)

1-phenyl-2-bromoethanol is also said to be a severe eye irritant in Pubchem, but not sure if it's as bad as bromacetophenone. The irritant mechanism of those alpha-haloketones is not the same as with capsaicinoids, and they can cause permanent damage in large concentrations.

 

[paracelsius]

so carbamethidine is a different drug entirely:

That's a different molecule altogether. Seems to be naming confusion. Wiki (and Canada Schedule) refer to “carbametidine” as another name for “oxpheneredine”!?? but that's a different compound! Is it also specifically excluded in Canada Schedule?.. looks pretty interesting. But the logP of that one seem rather very low, too polar imo (might not cross the BBB). Not sure how active it is as OP?!!

also alpha-bromoacetophenone would be reduced just as easily as oxo-oxpheneridine

yes but I was thinking about incomplete reduction in case one uses less than excess reducing agent to drive reaction to completion..but just speculation I don't know which route was used synthesize it.

sometimes it can set up the possibility for hydrogen bonding and hence stabilize the crystal form

yeah sometimes, especially when that makes crystal packing more symmetrical! I was thinking in terms of logP. Replacing H by a OH would usually decrease the logP by at least a whole log unit (10x more hydrophilic) + the OH H-bond donor/acceptor improves solvation in water (compare ethane v ethanol)
[/QUOTE]

..The irritant mechanism of those alpha-haloketones is not the same as with capsaicinoids, and they can cause permanent damage in large concentrations..

they're non-specitic electrophiles. will stick to any protein/biomolecules that happens to be around and do a lot of damage unlike capsaicins which target vanillinoid receptor specifically.

 

[sekio]

Wiki (and Canada Schelue) refer to “carbametidine” as another name for “oxpheneredine”!??

The Canadian drug law actually provides the "cortect" structure for carbamethidine. Wiki is in error. I fixed the oxpheneridine page and created a page for the correct name for this new compound: it is correctly called carperidine.

As for the structure, I know that a methyl carboxylate can be considered bioisosteric to a phenyl group, a la remifentanil. Maybe a carboxamide works similarly.