NOVEL LIGANDS SPECIFIC FOR MITOCHONDRIAL BENZODIAZEPINE RECEPTORS - 6-ARYLPYRROLO[2,1-D][1,5]BENZOTHIAZEPINE DERIVATIVES - SYNTHESIS, STRUCTURE-ACTIVITY-RELATIONSHIPS, AND MOLECULAR MODELING STUDIES

A novel class of ligands specific for MBR receptors has been identifie d: 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives. The majority of newly synthesized esters 37-64 as well as some intermediate ketones showed micro- or nanomolar affinity for [H-3]PK 11195 binding inhibit ion. ASAR study on 42 compounds and a molecular modeling approach led to a preliminary structural selectivity profile: the 6,7-double bond, the carbamoyloxy, alcanoyloxy, and mesyloxy side chains at the 7-posit ion, and the prospective chloro substitution at the Li-position seemed to be the most important structural features improving affinity. Ther efore, 7-[(dimethylcarbamoyl)oxy]- and -chloro-6-phenylpyrrolo[2,1-d][ 1,5]benzothiazepine (43 and 57) were synthesized. With p-methoxyphenyl )pyrrolo[2,1-d][1,5]benzothiazepine (65), these were the most promisin g compounds with IC(50)s of respectively 9, 8, and 9 nM, under conditi ons where PK 11195 had an IC50 of 2 nM.