MAPPING THE PERIPHERAL BENZODIAZEPINE RECEPTOR-BINDING SITE BY CONFORMATIONALLY RESTRAINED DERIVATIVES OF ETHYL-N-(1-METHYLPROPYL)-3-ISOQUINOLINECARBOXAMIDE (PK11195)

A synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PER) ligands related to 1-(2-chlo rophenyl)-N-methyl-N-(1-methylpropyl)-3- isoquinolinecarboxamide (PK11 195, 1) within their receptor has been developed. A wide series of con formationally restrained derivatives of 1 has been designed with the a im of probing the PER binding site systematically. The synthesis of th ese compounds involves palladium-catalyzed coupling and amidation as t he key steps. Twenty-nine rigid and semirigid derivatives of 1 were te sted in binding studies using [H-3]-1, and most of these showed PER af finities in the nanomolar range. The essential role of the carbonyl mo iety as a primary pharmacophoric element in the recognition by and the binding to PER has been confirmed, and the restricted range of the ca rbonyl orientations, which characterizes the most potent ligands, poin ts to a specific hydrogen-bonding interaction, mainly directed by the geometrical factors, when the electronic ones are fulfilled. Moreover, the fundamental importance of the short-range dispersive interactions in the modulation of the binding affinity and, hence, in the stabiliz ation of the ligand-receptor complex, emerged from the QSAR models rep orted.