1-Aminomethylbenzocycloalkanes: conformationallyrestricted hallucinogenic phenylamine analogues as functionally-selective 5-HT2A receptor agonists

McLean, Thomas H., Parrish, Jason C., Braden, Michael R., Marona-Lewicka, Danuta, Gallardo-Godoy, Alejandra and Nichols, David E. (2006) 1-Aminomethylbenzocycloalkanes: conformationallyrestricted hallucinogenic phenylamine analogues as functionally-selective 5-HT2A receptor agonists. Journal of Medicinal Chemistry, 49 19: 5794-5803. doi:10.1021/jm060656o


Author McLean, Thomas H.
Parrish, Jason C.
Braden, Michael R.
Marona-Lewicka, Danuta
Gallardo-Godoy, Alejandra
Nichols, David E.
Title 1-Aminomethylbenzocycloalkanes: conformationallyrestricted hallucinogenic phenylamine analogues as functionally-selective 5-HT2A receptor agonists
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2006-09-21
Sub-type Article (original research)
DOI 10.1021/jm060656o
Volume 49
Issue 19
Start page 5794
End page 5803
Total pages 10
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
A series of conformationally restricted analogues of the hallucinogenic phenethylamine 1 (2,5-dimethoxy-4-bromophenethylamine, 2C-B) was synthesized to test several hypotheses concerning the bioactive conformation of phenethylamine ligands upon binding to the 5-HT2A receptor. These benzocycloalkane analogues were assayed for their receptor binding affinity and ability to activate downstream signaling pathways, and one exceptional compound was selected for testing in an in vivo drug discrimination model of hallucinogenesis. All compounds were examined in silico by virtual docking into a homology model of the 5-HT2A receptor. On the basis of these docking experiments, it was predicted that the R enantiomer of benzocyclobutene analogue 2 would be the most potent. Subsequent chemical resolution and X-ray crystallography confirmed this prediction, as (R)-2 proved to be equipotent to LSD in rats trained to discriminate LSD from saline. Thus, we propose that the conformation of 2 mimics the active binding conformation of the more flexible phenethylamine type hallucinogens. In addition, (R)-2 is one of the most potent and selective compounds yet discovered in the in vivo drug discrimination assay. Further, 2 was found to be a functionally selective agonist at the 5-HT 2A receptor, having 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are correlated with arachidonic acid production, such functionally selective 5-HT2A receptor agonists may lack the intoxicating properties of hallucinogens such as LSD.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Fri, 01 Mar 2013, 13:58:26 EST by Susan Allen on behalf of Institute for Molecular Bioscience