Mapping and fitting the peripheral benzodiazepine receptor binding site bycarboxamide derivatives. Comparison of different approaches to quantitative ligand-receptor interaction modeling

The synthetic-computational approach to the study of the binding site of pe ripheral benzodiazepine receptor (PBR) ligands related to 1-(2-chlorophenyl ) -N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195, 1) withi n their receptor (Cappelli et al. J. Med. Chem. 1997, 40, 2910-2921) has be en extended. A series of carboxamide derivatives endowed with differently s ubstituted planar aromatic or heteroaromatic systems was designed with the aim of getting further information on the topological requisites of the car bonyl and aromatic moieties for interaction with the PER binding site. The synthesis of most of these compounds involves Weinreb amidation of the appr opriate lactone as the key step. The most potent compound, among the newly synthesized ones, shows a nanomolar PER affinity similar to that shown by I and the presence of a basic N-ethyl-N-benzylaminomethyl group in S-positio n of the quinoline nucleus. Thus, it may be considered the first example of a new class of water soluble derivatives of 1. Several computational metho ds were used to furnish descriptors of the isolated ligands (indirect appro aches) able to rationalize the variation in the binding affinity of the enl arged series of compounds. Sound QSAR models are obtained by size and shape descriptors (volume approach) which codify for the short-range contributio ns to Ligand-receptor interactions. Molecular descriptors which explicitly account; for the electrostatic contribution to the interaction (CoMFA, CoMS IA, and surface approaches) perform well, but they do not improve the quant itative models. Moreover, useful hints for the identification of the antago nist binding site in the three-dimensional modeling of the receptor (direct approach) were provided by the receptor hypothesis derived by the pharmaco phoric approach. The ligand-receptor complexes obtained provided a detailed description of the modalities of the interaction and interesting suggestio ns for further experiments.