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

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In the present study, as an attempt to locate new antiepileptic agent(s) with less side effects as well as toxicity, a new series of N-substituted-2- oxopyrrolidine derivatives was synthesized as GABA prodrugs and evaluated for their anticonvulsant activity adopting various screening models. N(4- Fluorobenzyl)-2-(2-oxopyrrolidin-1-yl)acetamide (14) proved to possess a potent broad spectrum anticonvulsant activity with wide safety margin, compared with valproic acid. Compound 14 is more potent (ED50 = 0.43 vs 0.71 mmol/kg for valproate) 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-Methoxybenzyl)-2-(2-oxopyrrolidin-1-yl)acetamide (15), N-(phenylethyl)-2-(2-oxopyrrolidin-1-yl)acetamide (16) and N-[2-(4- fluorophenyl)ethyl]-2-(2-oxopyrrolidin-1-yl)acetamide (17) are also among the potent derivatives found in this investigation. Compounds 14-17, however, have lipophilicity Log (p) values of 0.12-0.68 which is lower than that of valproate. The finding that compounds 14-16 protect against bicuculline- induced convulsions, confirms the rationale behind the design of the present series of compounds as GABA prodrugs.

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