A BENZODIAZEPINE RECOGNITION SITE ASSOCIATED WITH THE NON-NMDA GLUTAMATE RECEPTOR

GYKI 52466 is a benzodiazepine molecule that has muscle relaxant and anticonvulsant properties not attributable to a gamma-aminobutyric acid receptor-mediated mechanism. Here it is shown that GYKI 52466 exerts no blocking action at N-methyl-D-aspartate (NMDA) glutamate receptors, but acts noncompetitively to block ion currents and associated excitotoxicity, including ischemic neuronal degeneration, mediated through non-NMDA glutamate receptors. The inhibition of non-NMDA responses by GYKI 52466 is antagonized by cyclothiazide, hydrochlorothiazide, and diazoxide, benzothiadiazide drugs that inhibit non-NMDA receptor desensitization. These results suggest that non-NMDA receptor-ion channel complexes may contain a novel benzodiazepine recognition site where receptor desensitization is regulated; this postulated site represents a promising new target for rational development of drugs to treat neurological disorders.