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Novel mu-agonist/delta-antagonist opioids

wilson

Bluelighter
Joined
Dec 23, 2000
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There are a couple of interesting, but quite obscure and unassayed, opioids that are potent mu agonists and delta antagonists. Amazingly, this seems to prevent (or at least highly reduce) development of tolerance to at least the antinociceptive/pain-killing properties, which as far as I know is mediated through the same opioid receptor subtype (mu[1]) as the euphoria! I'm unable to find any research as to which degree this lack of tolerance development also applies to the euphoria (which isn't too surprising considering it's seen as an unwanted side effect of opioids...) but it definitely seems interesting.

Obviously there is going to be some development of tolerance to the euphoric qualities due to other feedback mechanisms (such as downregulation of the DAergic transmission in the nucleus accumbens), but this would probably be to a much lesser degree than the tolerance developed to normal opioids/opiates.

Most of these substances are peptides, but one interesting non-peptide one is 'SoRI 9409' (5'-(4-chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5alpha -epoxypyrido-[2',3':6,7]morphinan), which was first synthesized and assayed for opioid receptor affinity by Ananthan et al. (1999), and whose reduced antinociceptive tolerance development in vivo was confirmed by Wells et al. (2001).


Is anyone else as excited by these opioids as I am? We're talking legal, potent opioids which (possibly) doesn't cause much of a tolerance! Especially SoRI 9409 looks promising, as it seems to be possible to synthesize using a relatively simple route from commonly available and unwatched precursors - however, as it'd probably be against the forum rules, I won't go into the specifics here.

Maybe someone should synth. and bioassay various novel opioids (including SoRI 9409 and its' analogues) and make an OpioidsIHKAL :-). It's somewhat unfortunate that most underground chemists/psychopharmacologists are so focused on entheogens, which I guess is the reason these opioids haven't received much - if any - attention from the community.

So - what do you guys think? Can these substances be expected to be enjoyable - and continue to be so without the steep increase in dosage normally needed with opioids if used regurlarly? Obviously I'm not expecting that one would be able to use them 24/7 and achieve a constant state of euphoria, but still...


References:
Ananthan S, et al. (1999) Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans. J Med Chem 42: 3527-3538
Wells JL, et al. (2001) In vivo pharmacological characterization of SoRI 9409, a nonpeptidic opioid mu-agonist/delta-antagonist that produces limited antinociceptive tolerance and attenuates morphine physical dependence. Pharmacol Exp Ther. 297:597-605.
 
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Sorry but I noticed you don't post here much. Three years almost since your last one?

Anyways, that's pretty interesting info there. Is this available or is one of those impossible to get novelties
 
dbailey11 said:
Sorry but I noticed you don't post here much. Three years almost since your last one?
Yeah - I've lurked occasionally, but didn't feel the need to post.
Anyways, that's pretty interesting info there. Is this available or is one of those impossible to get novelties
It's not actually available from anywhere as far as I know - hell, the substance is untested in man - but the synthesis definitely seems doable in a clandestine setting (although I'm not much of a chemist, so I can't comment on the practical issues involved).
 
IMHO it looks like a serious multistep-painintheass-synthesis. =D But I'm not very familiar with any potential commercially availible starting materials (please PM me if you want, because I became rather curious). However I doubt anything like that is going to hit the market unless good starting materials (which narrow down the synthetic pathway drastically) really are availible or if the product is extremely potent. My guess is also that it probably is patented for the next 10 years or so which would prevent sales.
 
this does look rather interesting, I'll read the papers, do you know of any review papers on opioid tolerance?
 
Yeah those compounds do look interesting. Along the same lines the ORL-1 antagonists look quite promising, apparently stimulation of the ORL receptor is involved in the development of tolerance to mu-agonists, and antagonists for this receptor block the development of tolerance, and boost the action of mu-agonists when coadministered.

One of the ORL-1 antagonists tested, JTC-801 even acts as an analgesic in its own right (in mice anyway), not sure how but perhaps it is boosting the activity of endogenous endorphins or something? Anyway looks like there is some very interesting research in new opioids coming out.

Ref: Nurulain Zaveri , Faming Jiang, Cris Olsen, Willma Polgar, and Lawrence Toll. Small-Molecule Agonists and Antagonists of the Opioid Receptor-Like Receptor (ORL1, NOP): Ligand-Based Analysis of Structural Factors Influencing Intrinsic Activity at NOP. The AAPS Journal 2005; 7 (2) Article 34 (http://www.aapsj.org).
 
the problem is you cant eat or smoke them
the best route is im, td, or iv, so, unless your already a junkie, well, why not just make fentanyl or other opiods if you have a lab?
and peptide snythesis can be a much bigger bitch than you may think. it can also be a lot easier.
 
Not all of these compounds are peptides, and JTC-801 is orally active. Besides many compounds that are usually injected will be active if you snort them up your nose, albeit less potent. Even some peptides have been commercially developed as nasal sprays, vasopressin for instance.

Certainly these compounds are not easy to make, but the attraction is that they are very structurally distinct and so will not be illegal, even if you live in a jurisdiction with ridiculously wide controlled substance analogue laws. Besides what i liked about the ORL-1 antagonists is that its a completely new target so as recreational drugs such compounds would feel distinct from any other drugs used to date.
 
generally one needs something to open the tight junctions between cells to get anything of size to pass through the mucosal membranes (buccal or nasal)
 
mad_scientist said:
Certainly these compounds are not easy to make, but the attraction is that they are very structurally distinct and so will not be illegal, even if you live in a jurisdiction with ridiculously wide controlled substance analogue laws.
I'd expect SoRI 9409 to be covered by analog laws because of its morphinan skeleton, have I missed something?
 
Well its really impossible to say whether SoRI 9409 would be judged "substantially similar" or not...on the one hand its derived from naltrexone, which is not listed on the schedules, and its had a whole aromatic ring added on which is quite a substantial change in my opinion...but on the other hand it does share the basic morphinan skeleton and it displays mu-agonist properties, so your guess is as good as mine. I suspect it would be legal to import in the first instance but that would quickly change if they busted someone selling it...
 
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