TY - JOUR
T1 - A benzodiazepine recognition site associated with the non-NMDA glutamate receptor
AU - Zorumski, Charles F.
AU - Yamada, Kelvin A.
AU - Price, Madelon T.
AU - Olney, John W.
N1 - Funding Information:
This work was supported in part by National Institute of Mental Health Research Scientist Award MH38894 (J. W. O.), Research Scientist Development Award MHO0964 (C. F. Z.), Clinical Scientist Development Award NS01443 (K. A. Y.), and grants MH45493 and AG05681. GYKI 52466 was a generous gift of Dr. I. Tarnawa. Cyclothiazide was a generous gift of Eli Lilly and Company.
PY - 1993/1
Y1 - 1993/1
N2 - GYKI 52466 is a benzodiazepine molecule that has muscle relaxant and anticonvulsant properties not attributable to a γ-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.
AB - GYKI 52466 is a benzodiazepine molecule that has muscle relaxant and anticonvulsant properties not attributable to a γ-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.
UR - http://www.scopus.com/inward/record.url?scp=0027464959&partnerID=8YFLogxK
U2 - 10.1016/0896-6273(93)90242-J
DO - 10.1016/0896-6273(93)90242-J
M3 - Article
C2 - 8427702
AN - SCOPUS:0027464959
SN - 0896-6273
VL - 10
SP - 61
EP - 67
JO - Neuron
JF - Neuron
IS - 1
ER -