Synthesis and anticonvulsant activity of some 1-substituted-2-oxopyrrolidine derivatives, II.

In the present study, as an attempt to locate new antiepileptic agent(s) wi th less side effects as well as toxicity, a new series of N-substituted-2-o xopyrrolidine derivatives was synthesized as GABA prodrugs and evaluated fo r their anticonvulsant activity adopting various screening models, N-(4-Flu orobenzyl))-2-(2-oxopyrrolidin-1-y (14) proved to possess a potent broad sp ectrum anticonvulsant activity with wide safely margin, compared with valpr oic acid. Compound 14 is more potent (ED50 = 0.43 vs 0.71 mmol/kg for valpr oate) and has a higher protective index against convulsions (PI = 2.81 vs 1 .4-2.36 for valproate). Compound 14 with doses up to 0.5 and 1.0 g/kg i.p., did not produce mortality within 24 h after administration. N-(4-Methoxybe nzyl)-2-(2-oxopyrrolidin-1-yl)acetamide (15), N-(phenylethyl)-2-(2-oxopyrro lidin-1-yl)acetamide (16) and N-[2-(4-fluorophenyl)ethyl]-2-(2-oxopynolidin -1-yl)acetamide (17) are also among the potent derivatives found in this in vestigation. Compounds 14-17, however, have lipophilicity Log (p) values of 0.12-0.68 which is lower than that of valproate. The finding that compound s 14-16 protect against bicuculline-induced convulsions, confirms the ratio nale behind the design of the present series of compounds as GABA prodrugs.