Molecular Pharmacology, Vol 11, 833-840, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Neuroleptic Agents of the Benzocycloheptapyridoisoquinoline Series

A Hypothesis on Their Mode of Interaction with the Central Dopamine Receptor

¹ Department of Chemistry, Ayerst Research Laboratories, Montreal, Quebec, Canada H3C 3J1
² Department of Pharmacology, Ayerst Research Laboratories, Montreal, Quebec, Canada H3C 3J1

Two members of the novel benzocycloheptapyridoisoquinoline class of neuroleptic agents, one of them being the clinically active butaclamol, have been resolved into their enantiomers. Psychopharmacological studies on the antagonism of amphetamine-induced stereotyped behavior show that activity resides solely in the (+) enantiomers, which are at least 100 times more active than the (-) enantiomers. These results, as well as biochemical studies in vitro (published elsewhere), indicate that these compounds are central dopamine receptor antagonists. Based on the crystal structures of butaclamol and dexclamol, an optically active congener of butaclamol, and on the crystal structure of the dopamine receptor agonist apomorphine, quantitative conformational analyses were carried out on these semirigid ligands. The results reveal a striking similarity in the distances between the nitrogen and the phenyl ring plane of the extended phenethylamine moieties of apomorphine and of one of the conformers of butaclamol and dexclamol. This similarity suggests a mode of interaction of these ligands with a common primary binding site on the dopamine receptor. Important contributory interactions between other structural features of the butaclamol and dexclamol molecules with accessory binding sites on the dopamine receptor macromolecule were identified. The significance of the unique absolute configurations of the asymmetrical centers in dexclamol is explained in terms of a nonenantiomeric topography of adjacent areas on the dopamine receptor macromolecule.