1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists.

A series of rigid analogues of the hallucinogenic phenethylamine 2C-B was synthesized to determine the active shape these molecules adopt when binding to the 5-HT(2A) receptor. Computer docking predicted that one benzocyclobutene analogue, (R)-2, would be the most potent. Chemical resolution and X-ray crystallography confirmed this: (R)-2 was equipotent to LSD in rats trained to discriminate LSD from saline, making it one of the most potent and selective compounds yet tested in this assay. The compound also acted as a functionally selective agonist at the 5-HT(2A) receptor, showing 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are linked to arachidonic acid production, such selective agonists might lack the intoxicating properties of LSD.

Study at a glance

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-HT(2A) 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-HT(2A) 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-HT(2A) receptor agonists may lack the intoxicating properties of hallucinogens such as LSD.