RELATIONSHIP BETWEEN ANTICONVULSANT ACTIVITY AND PLASMA-LEVEL OF SOME2,3-BENZODIAZEPINES IN GENETICALLY EPILEPSY-PRONE RATS

The anticonvulsant effects of some novel 2,3-benzodiazepines acting as pha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid/kainate (AMPA /KA) antagonists were evaluated in genetically epilepsy prone rats. Th e ED50 values against clonic and tonic seizures (in mu mol/kg) reveale d that the rank order of anticonvulsant activity was: GYKI 52466 > 2,3 BZ-2 > 2,3 MBZ-2 > NBQX. Maximal anticonvulsant protection was observe d 15-45 min after the IP administration of NBQX and GYKI 52466, 30-90 min after the IP 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 obs erved 15 min after IP administration, 2,3BZ-2 revealed that peak plasm a concentration was achieved 45 min after IP administration, whereas f ollowing 2,3MBZ-2 administered IF, two curves were detected; one is re ferred to the parent compound and the other to its demethylate metabol ite that corresponds to 2,3BZ-2. The therapeutic index (ratio of TD50 values for impaired rotarod performance and ED50 values for anticonvul sant activity) revealed that NBQX and GYKI 52466 were slighly more tox ic than 2,3BZ-2 and 2,3MBZ-2. The present data suggest that 2,3-benzod iazepines acting at AMPA/kainate receptors play an important role in t he generation and/or propagation of the audiogenic seizures in genetic ally epilepsy-prone rats. (C) 1998 Elsevier Science Inc.