5-HT2a Highest Efficacy Agonists

[endotropic]

I have a question for all of you experts on psychedelics out there. We're all pretty familiar with the 5-HT2a agonists with the highest POTENCIES (LSD, Br-DFly, the NBOMe's, etc.), but I'm interested in the agonists with the highest measured intrinsic EFFICACY at the 5-HT2a receptor. Are these drugs even psychedelics, or do full efficay agonists at this receptor have some other effect?

My apologies ahead of time for not bringing any background research to this thread, but pubmed searches for things like "5-ht2a full agonists" or "5-ht2a highest efficacy" don't bring back anything relevant on the first couple of pages.

 

[sekio]

Efficacy at what? The 5-HT2Ar can be activated in several ways if i remember correctly.

The PLOS One study used Ca++ release. It said that, essentially, 5-meo-dmt and the higher-powered phenethylamines (DOB, DOI, 2c-e, 2c-t-2) all have activity at the receptor >90% that of serotonin.
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009019#pone.0009019.s006

Curiously psilocin is only a partial agonist with 70% activity at 5-ht2a.

Potency is a very important factor though. Even "inactives" like 4c-t-2 have high Emax values (100+).

 

[endotropic]

So I guess that paper sort of answers my question, but I think you have to take into account how far downstream Ca2+ release is from receptor activation. With that many steps in between, the amount of signal amplification will make partial agonists and full agonists fairly indistinguishable. I'll poke around a bit more and see if I can't find something directly measuring G-protein activation with different agonists, although I'm not sure whether anyone here besides me is interested in this kind of stuff haha.

In either case its still interesting that even with all of the steps between the receptor and the Ca2+ psilocin and some of the other STILL can't produce a maximum response. I wonder how much that kind of difference contributes to the subjective effects of psilocin vs. DOI for example?


Edit: Oh and to answer the efficacy at what question, when I think of intrinsic efficacy at GPCRs I think of things like G-protein activation and B-arrestin recruitment, things that are more or less directly coupled to receptor activation.

 

[cryptix420]

I think aniracetam interacts with this receptor.

 

[Cortexiphan]

You should take a look at this paper then. It discusses the relationship between the upstream activation of the Gq/11 protein and the downstream Ca++ release.

 

[endotropic]

Cortex that paper is exactly the kind of thing I was looking for. It's really interesting how they treat the Ca2+ response and Gq activation as independently regulated events, when my understanding of the pathway is: Gq activation -> PLC activation -> IP3 + DAG formation -> Ca2+ influx, but based on their data some other effector must be regulating Ca2+ release as well.

What really fascinates me is that 5-HT2a partial agonists like Lisuride are completely void of psychedelic effects, while 5-HT2a partial agonists like LSD are abundantly psychedelic. Does anyone know of another pathway downstream of 5-HT2a activation where LSD might be acting as an agonist while Lisuride acts as an antagonist? Beta-arrestin recruitment maybe?

 

[Cortexiphan]

Cortex that paper is exactly the kind of thing I was looking for. It's really interesting how they treat the Ca2+ response and Gq activation as independently regulated events, when my understanding of the pathway is: Gq activation -> PLC activation -> IP3 + DAG formation -> Ca2+ influx, but based on their data some other effector must be regulating Ca2+ release as well.

What really fascinates me is that 5-HT2a partial agonists like Lisuride are completely void of psychedelic effects, while 5-HT2a partial agonists like LSD are abundantly psychedelic. Does anyone know of another pathway downstream of 5-HT2a activation where LSD might be acting as an agonist while Lisuride acts as an antagonist? Beta-arrestin recruitment maybe?

Yeah, I thought the transduction pathway downstrem from Gq was settled, but maybe the ligands that exhibit that behavior are activating other receptors which also mediates intracellular Ca++ release. The ligands in the paper are not very selective so that is very likely.

There has been some papers from Stuart Sealfons group at Mount Sinai where they try to elucidate the mechanism of hallucinogenesis and I think it had something to do with some ligands stabilizing a heteromeric complex of the 5-HT2A and mGluR2/3 receptors (I`m not totally sold on this, but there you are) Link Link Link