AWD-140-190 - A NEW ANTICONVULSANT WITH A VERY GOOD MARGIN OF SAFETY

The anticonvulsant activity of the novel drug AWD 140-190 -bromophenyl )-3-morpholino-1H-pyrrole-2-carboxylic acid methyl ester) was evaluate d in animal models of epileptic seizures. AWD 140-190 was active at no ntoxic doses after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests. The compound was active agai nst electrically-induced seizures (MES, ED50 rat p.o. = 2.47 mg/kg), i n a genetic animal model the DBA/2 mouse, and in corneally kindled rat s. It was not active against seizures induced chemically by pentylenet etrazole, bicuculline and strychnine. Effective doses in mice followin g both oral and intraperitoneal administration are similar indicating good oral absorption. During 14 days chronic oral treatment of mice wi th 10 mg/kg, no development of tolerance was observed. The protective indices (TD50/MES ED50) in rats and mice following oral administration are favorable when compared to phenytoin, carbamazepine and valproate . No motor impairment, evaluated with the rotarod test and by observat ion in the open field test, was observable following oral administrati on of doses up to 500 mg/kg. There was no influence on spontaneous mot ility and learning performance in rats and no interaction with ethanol in mice after administration of doses which are above anticonvulsant effective doses indicating the absence of central side effects. AWD 14 0-190 thus presents an orally active and safe anticonvulsant agent, wh ich is structurally unrelated to anticonvulsants currently used. (C) 1 997 Elsevier Science B.V.