Structure-activity relationship investigations of the modulating effect ofcore substituents on the affinity of pyrazoloquinolinone congeners for thebenzodiazepine receptor

A series of 6- and 7-substituted-2-arylpyrazolo[4,3-c]quinolin-3-ones was s ynthesized and tested in vitro for binding with the benzodiazepine receptor in competition with [H-3]flunitrazepam. Electronic parameters (molecular e lectrostatic potential (MEP), charge distribution on the nitrogen atoms, di pole moment mu, and ionization potential (IP)) were calculated for the comp ounds by semi-empirical quantum chemistry methods. Lipophilicity of the com pounds, expressed as logarithm of the octanol-water partition coefficient ( log P), was calculated by the program Pallas. A quantitative correlation of the biological data with molecular parameters revealed a significant depen dence (r = 0.95) of the activity on hydrophobic constants of the substituen ts, log P, and magnitude of the MEP minimum associated with the carbonyl ox ygen atom. (C) 1998 Elsevier Science S.A. All rights reserved.