A CONCERTED STUDY USING BINDING MEASUREMENTS, X-RAY STRUCTURAL DATA, AND MOLECULAR MODELING ON THE STEREOCHEMICAL FEATURES RESPONSIBLE FOR THE AFFINITY OF 6-ARYLPYRROLO[2,1-D][1,5]BENZOTHIAZEPINES TOWARD MITOCHONDRIAL BENZODIAZEPINE RECEPTORS

The 7-(acyloxy)-6-arylpyrrolo[2,1-d][1,5]ben derivatives have been rec ently proposed as a new class of ligands specific for the mitochondria l benzodiazepine receptor (Fiorini et al. J. Med. Chem. 1994, 37, 1427 -1438) (Greco et al. J. Med. Chem. 1994, 37, 4100-4108). In this paper we report the X-ray crystallographic structures of three potent (1-3) and two inactive (4 and 5) previously described benzothiazepines, as well as binding affinity constants for two newly assayed analogs in wh ich the acyloxy side chain was replaced by a methoxy group (6) or remo ved (7). Structure-affinity relationships and molecular mechanics calc ulations performed using crystal structures as references have led to a revised 3D pharmacophore model accounting for all the data available up until now. Interestingly, the hypothetical receptor-bound conforma tions of 1-3 display a considerable degree of similarity with their cr ystal geometries. Additional calculations have confirmed that the poor affinities of benzothiazepines bearing an aroyloxy group (4 and 5) sh ould be ascribed to the steric and/or electronic features of the side chain aryl moieties rather than to unfavorable conformational properti es.