Is it me or do all the best drugs also work at the sigma receptor?
http://en.wikipedia.org/wiki/Sigma_receptor
http://en.wikipedia.org/wiki/Sigma_receptor
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N&PD Moderators: Skorpio
Sigma Receptor
- Thread starter ingo_1978
- Start date
any major dude
Bluelight Crew
lots of drugs effect it yes, but like above, whatever role this plays in the subjective experience of intoxication is not understood. Other receptors agonized by a whole pharmacopia but have ill understood subjective effects include: Imidazoline1, various Alpha sites, beta2, and 5ht1e to name a few.
If anybody has any info or speculation on what, if any, role those also play in subjective drug experiences feel free to wax neuropharmacologic.
pharmakos
Bluelighter
i don't know how it interacts with other drugs other than DXM. however, with DXM the sigma receptor gets activated after extended careless binging. i always thought of it as being there as a means of controlling drug use... if you go overboard your sigma receptors are going to get activated and you're going to be a bit nutty for awhile. intelligent design perhaps? ah... thats beyond the scope of ADD i think. =)greenmeanies
Bluelighter
- Joined
- Oct 8, 2009
- Messages
- 1,613
thenightwatch, are you confusing sigma receptor with sigma plateau? i always had the impression that 'sigma plateau' of DXM dosing was meant in the mathematical connotation of 'sigma', meaning 'the sum of' many repeated doses.
pharmakos
Bluelighter
dxm has a lower affinity for sigma receptors than for its other binding sites in your body. high concentrations of dxm are required for significant sigma binding to occur. many sigma ligands cause psychotic-like symptoms.
also worth looking up is the relation between the sigma receptor and amphetamine abuse/psychosis.
negrogesic
Bluelight Crew
While a number of recreational drugs have affinity, the sigma receptor does not seem to directly mediate any of the subjective euphoric properties of these drugs. DHEA is a strong sigma agonist but is devoid of any recreational potential. It is, however, said to have antidepressant properties, and is said to modulate the "reward" of drugs like cocaine. Note that "reward" and even "reinforcing" behavior seen in laboratory animals is not the same as the qualitative euphoria of recreational drugs. Some drugs can be highly addictive and induce strong reinforcing behavior but not be very euphoric, qualitatively speaking (like desoxypipradrol).
Here is a PDF discussing how neurosteroid sigma agonist like DHEA can "modulate" cocaine's rewarding properties: cocaine-sigma receptorLast edited:
acetylcholine
Bluelighter
I disagree that DHEA is a strong agonist. According to a review I have, its Ki is between 500 nM and 10 uM, not very strong at all when compared to the selective agonist Igmesine, or even Fluvoxamine, which both have Ki's of <50 nM (sigma1 subtype data).
I'd be fascinated to read about people's experiences with high doses of strong and selective sigma1 agonists. Weak agonists or unselective ones that also modulate very closely related systems like Glu-NMDA or DA have very limited utility in a subjective bioassay, imo.
P A
Bluelighter
I'd wager the effects would be pretty underwhelming, at least in reasonable doses - i.e., not risking seizures. If I remember right, there are at least a few quasi-selective, potent-ish ligands on the market at the moment - opipramol (mild serotonin/choline antagonism too, but whatever), berberine, and noscapine stand out as most selective/high-affinity. Never heard of any of those doing anything mind-blowing. Not to mention most drug isomers demonstrating higher selectivity for sigma receptors to the exclusion of others demonstrate little evidence of elevated abuse potential, at least in the absence of otherwise understandable instances of potentiation (NMDA antagonists and the like). Also, if it really were such big shit [as it's being touted in some of the literature], wouldn't you here more about fluvoxamine or sertraline or citalopram demonstrating significantly higher therapeutic efficacy, or even any substantial difference in effect? Other than the OCD-fluvoxamine thing, I'm not aware of anything striking...
As for the dissociatives though, relative sigma affinity probably has quite a bit to say with regard to potency and subjective differences among different drugs/enantiomers. And maybe, by extension, the dopaminergics too.
acetylcholine
Bluelighter
None of these appear to be available in the US. There seems to be a real lack of information on the subjective effects of selective sigma agonists.
I'd wager that opipramol, which is probably rare even in Germany, acts like your typical tricyclic antidepressant and for some reason, sigma agonism is mentioned in its mechanism of action, even if this agonism not much stronger than the sigma action of other TCAs. Besides, opipramol's anticholinergic and antihistamine action might make the sigma agonism hard to differentiate, at least at typical doses.
Berberine and glaucine are weirdo chemicals with multiple or unknown action, and I doubt that these can be used to gauge sigma action either.
NOSCAPINE sounds like it does have strong, selective sigma activation, and its effects might exemplify such action. I can't find any experience reports with noscapine either, though.
Interesting point, though efficacy might go either way depending on the patient and skew the statistics.
Anyway, I think you're probably right about sigma agonists not having strong cognitive or affective results.
P A
Bluelighter
Idea: 1. Score some primo diacetylmorphine, likely 'contaminated' with moderate quantities of the stubbornly persistent noscapine. Promptly inject. 2. While high, perform a fancy, as-of-yet unknown wash to remove/isolate the noscapine. Wait a while. Inject moar heroin. 3. Wait a few hours. Inject noscapine. 4. While on I.V. noscapine, report back.
Any chemfucks here? If so, how does?
Haoma
Greenlighter
It has been my observation that these sigma agonist work as a sort of amplifier of effects. It is the most intense drugs that seem to have sigma affinity. All the sigma agonist seem to be the ones that cause psychosis as well.
Sigma agonists reverse neuroplasticity in rodent models of shizophrenia.
sekio
Bluelight Crew
Haven't actually heard of any trip-reports of "pure" sigma agonists... anyone up for a +3-PPP voyage... lol
Nevermind then
At a sufficiently alkaline pH, the phenolic moiety of morphine (assuming hydrolysis of heroin-->morphine) will be deprotonated to its phenolate anion, and thus soluble in aqueous phase, while noscapine will remain in the organic phase (as it lacks any readily 'abstractable' protons)**.
So, if you take a blend of diacetlymorphine + noscapine and basify the sh*t out of it (pH approaching ~14), you will hydrolyze diacetylmorphine yielding the 3-phenolate morphine (anionic) and neutral noscapine**(maybe, see **note).
Extract with 3 x DCM (or related), wash with sat. bicarb, dry organic over mag sulf. strip to dryness affording Noscapine base. I'm pretty sloppy at the moment but that could be a viable route to crude noscapine from a heroin/noscapine blend.
**Assuming the lactone of noscapine doesn't hydrolyze under these highly basic conditions--which it likely would
Edit: also assuming you would have a crapload of heroin willing to destroy for the sake of research
Also, there are differences in solubility of morphine vs noscapine, as outlined in this patent involving a two solvent system:
http://www.google.com/patents/US20100081822Last edited:
