AWD 140-190: a potent anticonvulsant in the amygdala-kindling model of partial epilepsy.

Abstract

Evaluation of the effect of the new anticonvulsant drug, AWD 140-190 [4-(p-bromophenyl)-3-morpholino-1H-pyrrole-2-carboxylic acid methyl ester] on focally induced seizures and on epileptogenesis in the kindling model. Effects of AWD 140-190 were studied in amygdala kindled rats after oral and intraperitoneal administration. In addition, the effect on kindling development was evaluated. In all experiments, behavioral changes in the rats in response to AWD 140-190 were monitored closely. AWD 140-190 exerted potent anticonvulsant activity against focal seizures. After intraperitoneal and oral administration in fully kindled rats, the substance dose-dependently increased the threshold for induction of afterdischarges starting at 15 mg/kg. AWD 140-190 only weakly influenced the seizure severity of the animals after stimulation at the elevated afterdischarge threshold current. No adverse effects were observed up to 30 mg/kg after intraperitoneal and oral administration in the open field and in the rotarod test. No differences were found between kindled and nonkindled rats when comparing neurotoxicity of AWD 140-190. Prolonged treatment with AWD 140-190 during kindling acquisition did not prevent kindling, but significantly retarded the development of fully kindled seizures during the treatment. This study demonstrates that AWD 140-190 has anticonvulsant effects in the amygdala kindling model in rats, suggesting that the substance is particularly effective against partial seizures. AWD 140-190 is orally active and devoid of neurotoxic effects in anticonvulsant doses, thus indicating that this compound has potential for antiepileptic therapy. AWD 140-190 retards the kindling development during the treatment. This effect could be explained by the acute anticonvulsant effect of the substance.