Esters of isoguvacine as potential prodrugs

The syntheses of the methyl ester, butyl ester, (ethoxycarbonyl)methyl ester, and 11 (acyloxy)methyl esters of the potent gamma-aminobutyric acid agonist isoguvacine (1,2,3,6-tetrahydropyridine-4-carboxylic acid) and described. The chemical stability of the esters and their in vitro rates of hydrolysis under approximately physiological conditions by nonspecific esterases from human serum were examined. A selected number of the esters were tested for antagonism of convulsions induced by bicuculline, isoniazide, and by electroschock. While in the compounds showed only weak activities in the bicuculline and isoniazide tests, a good correlation between in vitro rates of enzymatic hydrolysis and the time of onset of the antagonism of the electroschock-induced convulsions could be found.