Investigation of novel antiepileptic drugs in animal seizure models is being carried out as a complement to studies on the interaction of these drugs with ion channels in in vitro systems. The anticonvulsant activities of a noncompetitive (GYKI[52466: 1~(4~aminophenyl)~4~methyl~7,8~methylenedioxy~5H~ 2,3~benzodiazepine) and a competitive (NBQX: 2,3~dihydroxy~6~nitro~7~ sulfamoyl~benzo[f]quinoxaline) non~NMDA (AMPA~kainate) excitatory amino acid antagonist were compared in the maximal electroshock (MES) seizure test and various chemoconvulsant models. Both antagonists were protective in the MES and pentylenetetrazol tests. GYKI[52466 was also protective against seizures and lethality induced by 4~aminopyridine, kainate and AMPA, but not by NMDA, whereas NBQX was ineffective in these chemoconvulsant tests. Both GYKI[52466 and NBQX produced motor impairment at doses similar to those that were protective in the MES test. We conclude that under some circumstances, noncompetitive AMPA~kainate antagonists could offer advantages over competitive antagonists in the treatment of seizures. However, neurological toxicity is an obstacle to the potential clinical use of both classes of agents. The effectiveness of AMPA~kainate antagonists in standard anticonvulsant screening models suggests that such compounds could have utility in epilepsy therapy. Noncompetitive AMPA~kainate antagonists, like GYKI[52466, may offer advantages over competitive antagonists in certain seizure types, especially those associated with high synaptic levels of glutamate.
Showing the most recent 10 out of 37 publications
