High affinity central benzodiazepine receptor ligands. Part 2: Quantitative structure-activity relationships and comparative molecular field analysisof pyrazolo[4,3-c]quinolin-3-ones

A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin-3(3 H)-ones (PQ, 106 compounds), carrying appropriate substituents at the quino line and N-2-phenyl rings, were designed, prepared and tested as central be nzodiazepine receptor ligands. Compounds with an affinity significantly hig her than the parent compound CGS-8216 were obtained, the most active ligand showing a pIC(50) = 10.35. Hansch and comparative molecular field analyses gave coherent results suggesting the main structural requirements of high receptor binding affinity. The possible formation of a three-centred hydrog en bond (HB) at the HB donor site H-2, as a key interaction for high recept or binding affinity, was assessed by the calculation and comparison of the molecular electrostatic potentials of a series of selected ligands. (C) 200 1 Elsevier Science Ltd. All rights reserved.