Mapping the Peripheral Benzodiazepine Receptor Binding Site by Conformationally Restrained Derivatives of 1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195)

Abstract

A synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PBR) ligands related to 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK11195, 1) within their receptor has been developed. A wide series of conformationally restrained derivatives of 1 has been designed with the aim of probing the PBR binding site systematically. The synthesis of these compounds involves palladium-catalyzed coupling and amidation as the key steps. Twenty-nine rigid and semirigid derivatives of 1 were tested in binding studies using [3H]-1, and most of these showed PBR affinities in the nanomolar range. The essential role of the carbonyl moiety as a primary pharmacophoric element in the recognition by and the binding to PBR has been confirmed, and the restricted range of the carbonyl orientations, which characterizes the most potent ligands, points 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 stabilization of the ligand-receptor complex, emerged from the QSAR models reported.

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with 1H/13C NMR Spectroscopy and Quantum Chemistry

“…35 A preference for TSPO to bind E rotamers would be consistent with the observation that TSPO invariably binds tertiary amides much more strongly than their corresponding secondary amides, as illustrated by several examples (Table S3, Supporting Information). 25,47 50 values for the binding of 1a and 1b, respectively, to TSPO.] The approximate energy parity of the Z and E rotamers of 1a, compared to the large energy disparity (5.8 kcal/mol) between the amide bond rotamers of 1b, might easily account for this binding energy difference.…”

Development of Ligands for the Peripheral Benzodiazepine Receptor

“…In an attempt to develop PBR ligands with more suitable kinetic profiles, a number of conformationally restrained isoquinoline-carboxamide derivatives of PK 11195 were synthesised [48]. The general structure of these VC compounds and their affinity compared to PK 11195 are shown in Fig.…”

Skeleton Diversity by Cyclopropanation of Tricyclic Acylenamines

“…The pyrroloazepinone partial structures of 21 and 23 occur in pyrrole-imidazole alkaloids related to the kinase inhibitor hymenialdisine [17]. Pyridoazepinones are much less frequent and have been synthesized as ligands of the peripheric benzodiazepine receptor [18].…”