Research on the pharmacochemistry of some GABA and valproic acid derivatives

Abstract

The role of GABA in epilepsy and especially in the action of various antiepileptics has been well established. We have reported the synthesis and pharmacochemical evaluation of a number of GABA and valproic acid derivatives and also the synthesis of two N-acyl-2-pyrrolidinone derivatives. We now report the pharmacochemical evaluation—anticonvulsant and antioxidant activity, and also study of lipophilicity—of the latter two in combination with the synthesis and evaluation of two novel ester derivatives (2-propylpentyl-3-pyridine carboxylate and 3-pyridinylmethyl 2-propylpentanoate), which contain the moieties of valproic acid and of 2-propyl-1-pentanol. Anticonvulsant activity was evaluated using the picrotoxin model and the antioxidant potential using the lipid peroxidation method. The study of lipophilicity was performed both by experimental (by reversed phase thin layer chromatography) and calculating (Rekker’s and Hansch/Leo’s fragmental and Suzuki/Kudo’s atom-based) methods; lipophilicity was also studied in combination with other physicochemical parameters of the above-mentioned compounds (van der Waals volume, van der Waals area, dipole moment, energy of formation, energy of hydration). In this study, we also include six other derivatives which we synthesized and tested in an earlier study. Only the two ester derivatives exhibited potent anticonvulsant and also antioxidant activity; the 2-pyrrolidinones did not exhibit significant activity in these experiments. In accordance with our earlier findings, the nicotinoyl and the nicotinyl moieties, in combination with considerable lipophilicity, seem to be suitable groups to confer activity in this type of compound. Good multiple correlation was derived between lipophilicity and energy of hydration and van der Waals volume of the compounds. Drug Dev. Res. 51:143–148, 2000. © 2001 Wiley-Liss, Inc.