Anticonvulsant activity and plasma level of 2,3-benzodiazepin-4-ones (CFMs) in genetically epilepsy-prone rats

Anticonvulsant properties of some 2,3-benzodiazepine derivatives acting as alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) antagonist s have been examined in vivo in the genetically epilepsy-prone rats using a n audiogenic seizures assay. 2,3-Benzodiazepin-4-ones (CFMs) are nonselecti ve AMPA antagonists that have been found to be potent anticonvulsant compou nd is in acute models of epilepsy. Because very little is known about their actions in a chronic model of epilepsy, and no correlations exist between anticonvulsant potency and plasma levels of these derivatives, we planned t o investigate such a relationship. Maximal anticonvulsant protection occurr ed 15-60 min after the IP administration of GYKI 52466, 30-90 min after CFM -2, and 45-120 min after CFM-3. In addition, maximal anticonvulsant effect was observed 60-120 min after the IP administration of CFM-4 and at 90 min after CFM-5. The therapeutic index revealed that GYKI 52466 was slightly mo re toxic than CFM-2 and CFM-3. The time course of plasma levels of rats tre ated showed that peak plasma concentration was observed 45 min after IP adm inistration of CFM-2 and CFM-3 and 75 min after CFM-4 and CFM-5. Following IP administration of CFM-3 two curves were detected, one is referred to the injected compound, and the other to its demethylated metabolite, which cor responds to CFM-2. Also, for the nitroderivative CFM-4 two curves were dete cted: one of an injected compound and the second due to its reduced metabol ite (CFM-2). Finally, three different metabolites were detected in rat plas ma after IP administration of CFM-5. The present study demonstrated that CF Ms showed a significant protection against auditory stimulation during the period of peak plasma concentrations, suggesting a marked inhibition of tho se brain structures involved in the initiation and/or spreading of the audi ogenic seizures. (C) 1999 Elsevier Science Inc.