MAPPING THE DOPAMINE RECEPTOR .2. FEATURES DERIVED FROM MODIFICATIONS IN THE RINGS A-B REGION OF THE NEUROLEPTIC BUTACLAMOL

Several analogues of the neuroleptic agent butaclamol having modifications in the rings A/B region of the molecule have been synthesized. Pharmacological evaluation identified the benzo[5, 6]cvclohepta analogue 2b, isobutaclamol, as being equipotent to butaclamol. The molecular structure of this compound has been analyzed, and the results have been used for mapping the central dopamine receptor. A planar catechol primary binding site, composed of α and β regions, has been identified and its minima! dimensions deduced. Its locus with respect to the nitrogen location site and its complementary hydrogen bond donor site has been specified. Using a Cartesian coordinate system, a receptor model is proposed which incorporates the above-mentioned features. The receptor model has been used to rationalize the observed chirality of the central dopamine receptor. © 1979, American Chemical Society. All rights reserved.