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.
Zorumski
C F
CF
Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri 63110.
Yamada
K A
KA
Price
M T
MT
Olney
J W
JW
D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000378:metabolism* / Q000494:pharmacology*; D001581:Benzothiadiazines / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D002478:Cells, Cultured; D002642:Chick Embryo; D004553:Electric Conductivity; D018691:Excitatory Amino Acid Antagonists; D006624:Hippocampus / Q000502:physiology; D007608:Kainic Acid / Q000494:pharmacology; D009410:Nerve Degeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017470:Receptors, Glutamate / Q000502:physiology*; D012160:Retina / Q000196:embryology / Q000502:physiology
D014151:Anti-Anxiety Agents; D001581:Benzothiadiazines; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; C061950:GYKI 52466; D001569:Benzodiazepines; D016318:Quisqualic Acid; C004639:cyclothiazide; D007608:Kainic Acid