RT Journal Article
SR Electronic
T1 Neuroleptic Activity of the 5-Aryltetrahydro-γ-carboline Series Conformational Requirements for Interaction with Central Dopamine Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 38
OP 42
VO 17
IS 1
A1 CHARLES A. HARBERT
A1 JACOB J. PLATTNER
A1 WILLARD M. WELCH
A1 ALBERT WEISSMAN
A1 B. KENNETH KOE
YR 1980
UL http://molpharm.aspetjournals.org/content/17/1/38.abstract
AB A series of novel 5-aryltetrahydro-γ-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-γ-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-γ-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 γ-carboline neuroleptics coalesce previously disparate proposals for the dopamine receptor interactions of butaclamol, diphenylbutylamines, and piperidylidene thioxanthenes.