1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists.
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.
McLean
Thomas H
TH
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907-1333, USA.
Parrish
Jason C
JC
Braden
Michael R
MR
Marona-Lewicka
Danuta
D
Gallardo-Godoy
Alejandra
A
Nichols
David E
DE
D000818:Animals; D016718:Arachidonic Acid / Q000096:biosynthesis; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004193:Discrimination Learning / Q000187:drug effects; D006213:Hallucinogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D008024:Ligands; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D008744:Methylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D058826:Serotonin 5-HT2 Receptor Agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C514172:(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine; D001643:Bridged Bicyclo Compounds; D006213:Hallucinogens; D007295:Inositol Phosphates; D008024:Ligands; D008744:Methylamines; D010627:Phenethylamines; D058826:Serotonin 5-HT2 Receptor Agonists; D016718:Arachidonic Acid; D008238:Lysergic Acid Diethylamide