Research on the pharmacochemistry of some GABA and valproic acid derivatives

The role of GABA in epilepsy and especially in the action of various antiep ileptics has been well established. We have reported the synthesis and phar macochemical evaluation of a number of GABA and valproic acid derivatives a nd also the synthesis of two N-acyl-2-pyrrolidinone derivatives. We now rep ort 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 conta in the moieties of valproic acid and of 2-propyl-1-pentanol. Anticonvulsant activity was evaluated using the picrotoxin model and the antioxidant pote ntial using the lipid peroxidation method. The study of lipophilicity was p erformed both by experimental (by reversed phase thin layer chromatography) and calculating (Rekker's and Hansch/Leo's fragmental and Suzuki/Kudo's at om-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 s ynthesized and tested in an earlier study. Only the two ester derivatives e xhibited potent anticonvulsant and also antioxidant activity; the 2-pyrroli dinones did not exhibit significant activity in these experiments. In accor dance 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 vo lume of the compounds Drug Dev. Res. 51:143-148, 2000. (C) 2001 Wiley-Liss, Inc.