• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio

mechanism of 2C-X compounds

With 2a partial agonists, wouldn't there be a great deal of sensitivity to small tweaks in experimental procedure that establish what rate of activity constitutes sufficient activation for agonism? So won't it depend on the particular assay, whether 2cs are found to be 2a antagonists or partial agonists?

I should shut up. I have one in my brain right now, and this is confusing. :D
 
I would expect a different 5ht2a receptor shape due to some developing 5-OH-DMT and 5-Meo-DMT. They don't want to start trippin out on their own venom.
 
Nexus298 said:
I would expect a different 5ht2a receptor shape due to some developing 5-OH-DMT and 5-Meo-DMT. They don't want to start trippin out on their own venom.
Click to expand...

5-MeO-DMT is mainly a 5-HT1a agonist, not a 5-HT2a one. besides, if their venom glands could hold the venom there, there'ld be no need to be resistent to their own venom, since it wouldn't enter their brain.
 
Xenopus oocytes are frog egg precursors. Here's an overview of how they're used in experiments:

http://faculty.plattsburgh.edu/donald.slish/Main.html

They're big, you can record electrical currents from them, and you can get them to express arbitrarily chosen receptors by injecting them with RNA. They'll insert the receptors into their membranes, and you can put a drug into the bath with them and record electrical activity in response. Receptors like the 5-HT2A receptor are "G protein coupled receptors," and they only cause currents indirectly, via G proteins and their downstream effects on ion channels.

In the paper mentioned by the OP, oocytes were made to express 5-HT2A or 5-HT2C receptors. Serotonin activated those receptors and caused a current, but this current was blocked in 5-HT2A-expressing cells if serotonin and 2C-I were co-applied. In that sense, 2C-X drugs antagonized an effect of serotonin. If you look at Figure 2 of the paper, you can see that 2C-I on its own also caused a current, but it wasn't nearly as big as the serotonin-evoked current. That's partial agonism, which the figure caption acknowledges. The drug mimics the natural ligand of the receptor, but it's not as effective. If a partial agonist and a full agonist are competing for a receptor, the effect of the full agonist will be partly blocked by the partial agonist, as we see here.
 
It's been known that the 2C's are partial agonists - i've seen a few tables posted about (can't find them, of course) of the efficacy of a few 2C's, as well as a few other psychedelics, at 5HT2A, and the 2C's are always lowest (with all of them having an efficacy at 5HT2A of less than 100% that of serotonin).


Are the concentrations used remotely sane? What is the binding affinity of serotonin itself at those receptors?

http://jpet.aspetjournals.org/content/304/1/229.long is worth a read - it was cited in the original article, and, while rather dense, looks like an interesting read.

Seems this just keeps getting more complicated.
 
You must log in or register to reply here.
Top