Relationship between anticonvulsant activity and plasma level of some 2,3-benzodiazepines in genetically epilepsy-prone rats.
The anticonvulsant effects of some novel 2,3-benzodiazepines acting as alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid/kainate (AMPA/KA) antagonists were evaluated in genetically epilepsy prone rats. The ED50 values against clonic and tonic seizures (in micromol/kg) revealed that the rank order of anticonvulsant activity was: GYKI 52466 > 2,3BZ-2 > 2,3 MBZ-2 > NBQX. Maximal anticonvulsant protection was observed 15-45 min after the i.p. administration of NBQX and GYKI 52466, 30-90 min after the i.p. administration of 2,3BZ-2, and 45-120 min after the i.p. administration of 2,3MBZ-2. The time course of plasma levels of rats treated with GYKI 52466 showed that peak plasma concentration was observed 15 min after i.p. administration, 2,3BZ-2 revealed that peak plasma concentration was achieved 45 min after i.p. administration, whereas following 2,3MBZ-2 administered i.p., two curves were detected; one is referred to the parent compound and the other to its demethylate metabolite that corresponds to 2,3BZ-2. The therapeutic index (ratio of TD50 values for impaired rotarod performance and ED50 values for anticonvulsant activity) revealed that NBQX and GYKI 52466 were slighly more toxic than 2,3BZ-2 and 2,3MBZ-2. The present data suggest that 2,3-benzodiazepines acting at AMPA/kainate receptors play an important role in the generation and/or propagation of the audiogenic seizures in genetically epilepsy-prone rats.
Department of Experimental and Clinical Medicine, School of Pharmacy, University of Catanzaro, Italy.
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood / Q000627:therapeutic use; D000927:Anticonvulsants / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D004827:Epilepsy / Q000097:blood / Q000517:prevention & control*; D009043:Motor Activity / Q000187:drug effects; D019957:Motor Skills Disorders / Q000188:drug therapy; D011810:Quinoxalines / Q000097:blood / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D011810:Quinoxalines; D018091:Receptors, AMPA; C061950:GYKI 52466; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001569:Benzodiazepines