Zorumski C F, Yamada K A, Price M T, Olney J W
Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri 63110.
Neuron. 1993 Jan;10(1):61-7. doi: 10.1016/0896-6273(93)90242-j.
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.
GYKI 52466是一种苯二氮䓬类分子，具有肌肉松弛和抗惊厥特性，并非由γ-氨基丁酸受体介导机制所致。本文表明，GYKI 52466对N-甲基-D-天冬氨酸（NMDA）谷氨酸受体无阻断作用，但通过非NMDA谷氨酸受体介导，以非竞争性方式阻断离子电流及相关的兴奋性毒性，包括缺血性神经元变性。GYKI 52466对非NMDA反应的抑制作用可被环噻嗪、氢氯噻嗪和二氮嗪（抑制非NMDA受体脱敏的苯并噻二嗪类药物）所拮抗。这些结果提示，非NMDA受体-离子通道复合物可能含有一个调节受体脱敏的新型苯二氮䓬识别位点；这一假定位点代表了合理开发治疗神经疾病药物的一个有前景的新靶点。
