Stereochemistry and Electronic structure of anticonvulsant drugs

Abstract

Anticonvulsant drugs come from a range of chemical types, but most drugs show important structural features in common. It has been suggested elsewhere that molecular conformation may be an important factor in determining activity. The present work has been designed to investigate the influence of both stereochemistry and electronic structure on anticonvulsant action. Empirical potential energy calculations are first used to determine preferred conformations. It is found that anticonvulsants adopt a common preferred conformation, which is likely to be responsible for anticonvulsant activity. Molecular electrostatic potentials are also calculated for anticonvulsants, after first being evaluated in a series of model compounds. Electrostatic potentials based on MINDO/3 wave functions are found to be well suited to molecules containing carbonyl groups, and are also able to provide a quantitative estimate of reactivity. Applications to anticonvulsants shows the existence of a common electrostatic field, where similar regions of positive and negative potential are seen throughout the series studied. The structure-activity relationship outlined here applies to anticonvulsant activity against experimental electroshock seizures, and associated clinical use in the treatment of tonic-clonic (grand mal) epilepsy. It appears that both stereochemical and electronic factors play an important role in determining the activity of anticonvulsant drugs.