The
anticonvulsant activity of the novel
drug AWD 140-190 (4-(p-bromophenyl)-3-morpholino-1H-pyrrole-2-carboxylic acid methyl ester) was evaluated in animal models of epileptic
seizures.
AWD 140-190 was active at nontoxic doses after oral and intraperitoneal administration in rats and mice in a range of
anticonvulsant tests. The compound was active against electrically-induced
seizures (MES, ED50 rat p.o. = 2.47 mg/kg), in a genetic animal model the DBA/2 mouse, and in corneally kindled rats. It was not active against
seizures induced chemically by
pentylenetetrazole,
bicuculline and
strychnine. Effective doses in mice following both oral and intraperitoneal administration are similar indicating good oral absorption. During 14 days chronic oral treatment of mice with 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 observation in the open field test, was observable following
oral administration of doses up to 500 mg/kg. There was no influence on spontaneous motility 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 140-190 thus presents an orally active and safe
anticonvulsant agent, which is structurally unrelated to
anticonvulsants currently used.