title: Computer-aided molecular modeling, synthesis, and biological evaluation of 8-(benzyloxy)-2-phenylpyrazolo[4,3-c]quinoline as a novel benzodiazepine receptor agonist ligand.
abstract: 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 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 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.
authors.affiliation: Department of Chemistry, Rutgers, State University of New Jersey, Newark 07102.
authors.forename: C G
authors.initials: CG
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: Langer
authors.forename: P G
authors.initials: PG
authors.lastname: Kamath
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Gu
authors.forename: P
authors.initials: P
authors.lastname: Skolnick
authors.forename: R I
authors.initials: RI
authors.lastname: Fryer
mesh_terms: D000818:Animals; D003198:Computer Simulation; D005069:Evaluation Studies as Topic; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D009010:Monte Carlo Method; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: C092760:8-(benzyloxy)-2-phenylpyrazolo(4,3-c)quinoline; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D011720:Pyrazoles; D015363:Quinolones