Esters of nipecotic and isonipecotic acids as potential anticonvulsants

A variety of esters of nipecotic and isonipecotic acids were synthesized and evaluated for anticonvulsant activity. The ester group was varied in terms of lipophilicity and reactivity toward hydrolysis. The esters were screened against seizures induced by electroshock, pentylenetetrazol, and the putative gamma-aminobutyric acid antagonist, bicuculline. The most significant activity was demonstrated by the p-nitrophenyl esters of nipecotic and isonipecotic acids against bicuculline-induced seizures. Esters of nipecotic acid were tested for in vitro inhibition of gamma-aminobutyric acid and L-proline uptakes into mouse whole brain minislices. The p-nitrophenyl, n-octyl, and succinimidyl esters were the most potent inhibitors of gamma-aminobutyric acid uptake. The uptake of gamma-aminobutyric acid by the ester derivatives appeared to involve specific and nonspecific mechanisms.