N&PD Moderators: Skorpio
Design, Synthesis, and Binding Affinity of Novel N-Naphthyl-Substituted Phenethylamines as 5-HT2AR Agonists
Didgital
Bluelight Crew
So this is a semi recent paper that I can't access fully. It describes a "new" class of super potent non psychedelic psychoplastogens that are PEAs with N-Napthyl groups.
Was wondering if anyone here could comment at all about it. How can they predict its non hallucinogenic is my question..
tuppingtoncity
Bluelighter
They seem to be associating high β-arrestin bias at 5-HT2a of these N-Naphthyl phenethylamines as evidence that they are non-hallucinogenic. It does seem to be the case that some manner of Gq recruitment during 2a signaling is necessary for classical psychedelic effects, so it wouldn't surprise me if they were indeed non-psychedelic (see this paper for a deeper exploration of biased signaling at 2a). As to their utility, that it is a debate for another day. I'm not particularly convinced of any clinical utility for exclusive-plasticity promoting compounds to be honest.
It is a conference abstract, thus the 'paper' is so short. I assume some sort of complete paper will be published in the future, N-naphthyl substituted phenethylamines seem like they would be a pretty fascinating group of compounds.
Didgital
Bluelight Crew
Me either, we can discuss it another time maybe in a couple years after these things have been trialled in healthy adults????
Thanks for the response, I'm not a pharmacologist and I don't know as much about beta arrestin as I could or should. I've always read about it in context of tolerance. I'll try and read up a bit on it and how it affects receptor groups.
MedicinalUser247
Bluelighter
Longer acting yes. Less Hallucinogenic no.
MedicinalUser247
Bluelighter
Here's only one example of a substance of that kind. Leaving a large window open to make a variety of N-Naphthylated substances. https://en.wikipedia.org/wiki/2C-G-N
tuppingtoncity
Bluelighter
The paper is referring to N-naphthylated phenethylamines (as in a naphthyl substituent on the phenethylamine nitrogen), not naphthyl-ethanamines like the few in the 2c-g series. These compounds have not been synthesized before to my knowledge, and if their supposed high β-arrestin bias is true, they are unlikely to be psychedelic in any meaningful sense.
Didgital
Bluelight Crew
.....
@MedicinalUser247 N-1-napthyl PEAs are what they are talking about. Specifically the top molecule (circled).
Completely diff drugs.
If anything the 2C-T2-1-Napthyl resembles an Nbome more closely than it does than anything in the 2C-G series.
Didgital
Bluelight Crew
Take a look. Entire 2C-G series was based and named off shulgins discovery of Ganesha and related compounds. It has substitutions (always carbon as far as i can tell) off both the 4 and the 3 positions. I didnt draw them all.
Pretty sure he named it Ganesha because Ganesha the hindu god has many arms.
He prolly shoukda called Ganesha 3C-G but Ganesha def cooler sounding.
Didgital
Bluelight Crew
Also the numbered 2C-gs, the number is referring to the number of extea carbons in the ring system(s) drawn in black balls.
Woulda struggled to draw 2C-G-5 before illustrating tbh.
Didgital
Bluelight Crew
That much I do know.
Affinity i see as how much the molecule wants to dock in the receptor.
Efficacy i see as the how much ability the molecules has to actually cause a response.
Is that basically true in laymens terms?
4DQSAR
Bluelighter
Superagonist<-agonist<-partial agonist<-silent agonist->inverse agonist->antagonist.
Now, what defines a supeagonist is simple, but not so clear with patrial agonist as some make bind in two or more conformations making them mixed agonists. Same with inverse agonist, it just demonstrates more antagonism than agonism.
Always try to get the EC50 value of a ligand as this can be more illustrative but functional MRI and functional PET are the best tools we have to know where a ligand actually binds in such a complex system as the human body. Lopramide has a Ki of 3.15 nM ± 1.5 nM (similar to morphine) but doesn't cross the BBB well and an active transport removes it from the brain. So Ki can tell you only a little.
It's something to know, certainly, but you would be amazed at how much has to be inferred and how far out of one specific scallfold one may have to look to find a key moiety. That's why I asked about BDPC experiences - I wish to understand the docking and active conformations and a user report WOULD be of value to science. Not to me specifically, but because we cannot perform such tests legally - hence we are ignorance.