STRUCTURAL AND ELECTRONIC FACTORS ASSOCIATED WITH THE ACTIVITY IN THEGABA-A SYSTEM

A structural and electronic analysis of GABA(A) analogs, either showin g agonist or antagonist activity, was performed at the ab initio (G94) HF/6-31 + G(d,p) level, modeling the surrounding physiological media as a continuum solvent (water), within an Onsager approach. The study has allowed us to define a pharmacophoric pattern for GABA(A) agonists , that reveals the following features: (i) a positively charged ammoni um group, bound to the hydrocarbon chain in a conformation close to th at defined by THIP; (ii) a negatively charged CO group whose conformat ion is similar for the set of compounds analyzed, and can be defined b y either muscimol or THIP; (iii) a distance between the ionized moieti es longer than 5.3 A. The latter condition, which is the most relevant contribution of this research, appears as determinant to differentiat e between agonist and antagonist activity. For the same set of compoun ds, calculations in vacuum have been performed in order to compare the ab initio results with those derived from semiempirical AMI, PM3 and MNDO methodologies. The coincidence between them supports the applicab ility of appropriately chosen semiempirical calculations for the confo rmational study of GABA(A) analogs. (C) 1998 Elsevier Science B.V. All rights reserved.