title: Anticonvulsant activity and plasma level of 2,3-benzodiazepin-4-ones (CFMs) in genetically epilepsy-prone rats.
abstract: Anticonvulsant properties of some 2,3-benzodiazepine derivatives acting as alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) antagonists have been examined in vivo in the genetically epilepsy-prone rats using an audiogenic seizures assay. 2,3-Benzodiazepin-4-ones (CFMs) are nonselective AMPA antagonists that have been found to be potent anticonvulsant compound 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 to investigate such a relationship. Maximal anticonvulsant protection occurred 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 more toxic than CFM-2 and CFM-3. The time course of plasma levels of rats treated showed that peak plasma concentration was observed 45 min after IP administration 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 corresponds to CFM-2. Also. for the nitroderivative CFM-4 two curves were detected: one of an injected compound and the second due to its reduced metabolite (CFM-2). Finally, three different metabolites were detected in rat plasma after IP administration of CFM-5. The present study demonstrated that CFMs showed a significant protection against auditory stimulation during the period of peak plasma concentrations, suggesting a marked inhibition of those brain structures involved in the initiation and/or spreading of the audiogenic seizures.
authors.affiliation: Department of Experimental and Clinical Medicine, University of Catanzaro, Italy.
authors.forename: G
authors.initials: G
authors.lastname: De Sarro
authors.forename: M
authors.initials: M
authors.lastname: Rizzo
authors.forename: C
authors.initials: C
authors.lastname: Spagnolo
authors.forename: R
authors.initials: R
authors.lastname: Gitto
authors.forename: A
authors.initials: A
authors.lastname: De Sarro
authors.forename: G
authors.initials: G
authors.lastname: Scotto
authors.forename: M
authors.initials: M
authors.lastname: Zappala
authors.forename: A
authors.initials: A
authors.lastname: Chimirri
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001569:Benzodiazepines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; C061950:GYKI 52466; D001569:Benzodiazepines