Computer-Aided Molecular Modeling, Synthesis, and Biological Evaluation of 8-(Benzyloxy)-2-phenylpyrazoloquinoline as a Novel Benzodiazepine Receptor Agonist Ligand

Article abstract of DOI:10.1021/jm00006a014

Using computer-aided conformational analysis, based on molecular dynamics simulation, cluster analysis, and Monte Carlo techniques, we have designed and synthesized compounds in which a benzyloxy substituent has been incorporated into a series of pyrazoloquinoline benzodiazepine receptor (BZR) ligands.Earlier studies had shown that the benzyloxy group could act as part of the agonist pharmacophoric determinant in the β-carboline ring system.Furthermore, the agonist β-carboline had been correlated with a binding site orientation and volume fit for an agonist 6-phenylimidazobenzodiazepine carboxylate.The present study was undertaken to determine whether the benzyloxy substituent could be used as an agonist pharmacophoric descriptor for the phenylpyrazolo<4,3-c>quinolin-3-one BZR ligands.The results of a determination of GABA shift ratios for the synthetic ligands indicate that 8-(benzyloxy)-2-phenylpyrazolo<4,3-c>quinolin-3-one can be predicted to be an agonist at the BZR.