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4-Methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists

C6H6

C6H6

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This paper might also disclose some 2-HT2A agonists which certainly emerged as side products. In case anyone can get hold of this paper, please post it.

Bioorg Med Chem Lett. 2005 Jun 20; [Epub ahead of print]

Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists.

Rover S, Adams DR, Benardeau A, Bentley JM, Bickerdike MJ, Bourson A, Cliffe IA, Coassolo P, Davidson JE, Dourish CT, Hebeisen P, Kennett GA, Knight AR, Malcolm CS, Mattei P, Misra A, Mizrahi J, Muller M, Porter RH, Richter H, Taylor S, Vickers SP.

Vernalis Research Ltd, Oakdene Court, 613 Reading Road, Wokingham RG41 5UA, UK.

Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.

PMID: 15975787
 
Thanks for posting the paper.

Well, compounds 1 and 6 are both full agonists at the 5-HT2A and 2C receptors with low and approximately equal nM affinity at the two receptors. I think there's a lot of reason to believe that they will be active as psychedelics. So this would be the first new chemical class with potential psychedelic activity beyond the PEAs, tryptamines and lysergic acid amides. If only they were simpler to make.
 
Damn 5-HT2C receptor... you can make selective 5-HT2C ligands, but where are the selective 5-HT2A agonists?
 
And it would have been an even much more amusing series if they would have been optimizing for 5-HT2A activity and not for 5-HT2C selectivity. Can't we get Bill Gates to fund some research in this direction?
 
their similarities to the "fly" type compounds is interesting. Were I the curious sort I believe I would be looking into them both for the sites of 5-Ht-2a activity. My gut says a whole bunch of new ,potent and possibly dangerous in the length of activity are on the way based on planar aromatics. Just a thought
WR
 
I think they have more in common with the phenylpiperazines. mCPP, 1(3-chlorophenyl)piperazine, is a known, non-selective 5-HT2 agonist with predominant activity at the 5-HT2C receptor. If you look at compound 1 in the paper, there you need to take out only one carbon and you have mCPP. These compounds are sort of rigidified phenylpiperazines.
 
i remember a few years ago people saying that in the future we will be able to regulate exactly how we want to feel with drugs highly slective towards certain binding sites. i thought it was a little too science fictiony at the time, but this looks like a step in that direction
 
^ Nah, those ideas are bullshit, pharmacology will never get that advanced... you can't just localization shit to a receptor, you need to localization to an area of the brain, and regulate the action temporally as well...
 
Well with plain pharmacology, it just can't be done. With pharmaco-nanotechnology, I can imagine a nano-bot either injection 100ths of femtomolar amounts of drugs into discrete areas, or just activating receptors direct, in a temporally and spatially choreographed manner...
 
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