1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists.
Thomas H. Mclean, Jason C. Parrish, Michael R Braden, Danuta Marona‐lewicka, Alejandra Gallardo-Godoy, David E Nichols
Journal of Medicinal Chemistry September 21, 2006 DOI: 10.1021/jm060656o (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with in vitro, in silico, and in vivo components Peer reviewed |
|---|---|
| Population | Rats trained to discriminate LSD from saline |
| Interventions | benzocyclobutene analogue 2 (R)-2 |
| Topics | LSD Serotonin |
| Keywords | Psychopharmacology: neuropharmacology Drug action Brain chemistry Receptor binding Signaling pathways Therapeutic potential Drug discovery Drug development Compound synthesis Phenethylamines Molecular design Medicinal chemistry Psychedelic research: hallucinogens Non-intoxicating psychedelics Therapeutic psychedelics Serotonergic agonists Drug prediction Molecular modeling |
| Citations | 115 |
| Key findings | The conformationally restricted analogue (R)-2 is equipotent to LSD in a rat drug discrimination model and is a functionally selective 5-HT(2A) receptor agonist with 65-fold greater potency for phosphoinositide turnover over arachidonic acid release. |
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.