CONFORMATIONAL-ANALYSIS, MOLECULAR MODELING, AND QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF AGENTS FOR THE INHIBITION OF ASTROCYTIC CHLORIDE TRANSPORT

Molecular modeling studies were carried out on a series of 1-oxoisoind olines which are pharmacologically active as inhibitors of astrocytic chloride transport. Conformational analysis revealed that the halogen substituent exerted a pronounced steric directing effect on the acid s ide chain. The 4-substituted analogs apparently provided for the best spatial arrangement of pharamacophoric elements of the molecules. Conv entional quantitative structure-activity relationship (QSAR) studies u sing lipophilic and dipole moment characteristics of the molecules as physical descriptor variables in the regression equation yielded a sta tistically significant model. Comparative molecular field analysis (Co MFA) was utilized as a three-dimensional QSAR technique to explore cha nge in the steric and electrostatic fields of the molecules that can a ccount for differences in biological activity values. A highly predict ive model was attained which supported the results from the qualitativ e and conventional quantitative structure-activity relationship analys es. These modeling techniques represent the evolutionary process by wh ich structure-activity methods were employed to aid in the development of novel more potent inhibitors of astrocytic chloride transport.