Molecular Pharmacology, Vol 17, 38-42, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Neuroleptic Activity of the 5-Aryltetrahydro--carboline Series Conformational Requirements for Interaction with Central Dopamine Receptors

¹ Department of Medicinal Chemistry, Pfizer Central Research Laboratories, Groton, Connecticut 06340
² Department of Pharmacology, Pfizer Central Research Laboratories, Groton, Connecticut 06340

A series of novel 5-aryltetrahydro--carboline neuroleptics is described. Their interaction with the dopamine receptor is demonstrated by their potent and long-lasting blockade of amphetamine-induced stereotyped behavior in rats and by the displacement of bound ³H-spiroperidol in vitro. The 5-aryl--carboline nucleus appears to be primarily responsible for receptor interaction while the side chain serves to extend duration, presumably by altering metabolism and/or tissue distribution. The conformation of the semirigid 5-aryl--carboline nucleus approximates that of the previously proposed active conformation of the open-chain diphenylbutylpiperidine neuroleptics. Comparison of the crystal structure of CP-36,584 with those of apomorphine and (+)-dexclamol suggests a common, conformationally restricted phenethylamine moiety as the species interacting with the receptor. Findings with the -carboline neuroleptics coalesce previously disparate proposals for the dopamine receptor interactions of butaclamol, diphenylbutylamines, and piperidylidene thioxanthenes.