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

Abstract 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 quinoline and N 2 -phenyl rings, were designed, prepared and tested as central benzodiazepine receptor ligands. Compounds with an affinity significantly higher 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 hydrogen bond (HB) at the HB donor site H 2 , as a key interaction for high receptor binding affinity, was assessed by the calculation and comparison of the molecular electrostatic potentials of a series of selected ligands.