COMPUTER-AIDED MOLECULAR MODELING, SYNTHESIS, AND BIOLOGICAL EVALUATION OF 8-(BENZYLOXY-2-PHENYLPYRAZOLO[4,3-C]QUINOLINE AS A NOVEL BENZODINZEPINE RECEPTOR AGONIST LIGAND

Using computer-aided conformational analysis, based on molecular dynam ics simulation, cluster analysis, and Monte Carlo techniques, we have designed and synthesized compounds in which a benzyloxy substituent ha s been incorporated into a series of pyrazoloquinoline benzodiazepine receptor (BZR) ligands, Earlier studies had shown that the benzyloxy g roup could act as part of the agonist pharmacophoric determinant in th e beta-carboline ring system. Furthermore, the agonist beta-carboline had been correlated with a binding site orientation and volume fit for an agonist 6-phenylimidazobenzodiazepine carboxylate. The present stu dy was undertaken to determine whether the benzyloxy substituent could be used as an agonist pharmacophoric descriptor for the phenylpyrazol o[4,3-c]quinolin-3-one BZR ligands, The results of a determination of GABA shift ratios for the synthetic ligands indicate that -(benzyloxy) -2-phenylpyrazolo[4,3-c]quinolin-3-one can be predicted to be an agoni st at the BZR.