Wong E H, Kemp J A, Priestley T, Knight A R, Woodruff G N, Iversen L L
Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104-8. doi: 10.1073/pnas.83.18.7104.
The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate. The potencies of phencyclidine, ketamine, SKF 10,047, and the enantiomers of MK-801 as N-Me-D-Asp antagonists correlated closely (r = 0.99) with their potencies as inhibitors of [3H]MK-801 binding. This suggests that the MK-801 binding sites are associated with N-Me-D-Asp receptors and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant.
化合物MK - 801[（+）-5 - 甲基 - 10,11 - 二氢 - 5H - 二苯并[a,d]环庚烯 - 5,10 - 亚胺马来酸盐]是一种强效抗惊厥药，口服后具有活性，但其作用机制尚不清楚。我们在大鼠脑膜中检测到了[3H]MK - 801的高亲和力（Kd = 37.2±2.7 nM）结合位点。这些位点对热不稳定、具有立体选择性且具有区域特异性，海马体中的位点密度最高，其次是大脑皮层、纹状体和延髓 - 脑桥。在小脑中未检测到结合。MK - 801结合位点呈现出一种新的药理学特征，因为主要的神经递质候选物在这些位点均无活性。唯一能够竞争[3H]MK - 801结合位点的化合物是已知能阻断由N - 甲基 - D - 天冬氨酸（N - Me - D - Asp）受体亚型介导的兴奋性氨基酸反应的物质。这些物质包括分离麻醉剂苯环己哌啶和氯胺酮以及σ型阿片类药物N - 烯丙基去甲左啡诺（SKF 10,047）。使用大鼠皮层切片制备物进行的体外神经生理学研究表明，MK - 801对N - Me - D - Asp的去极化反应具有强效、选择性和非竞争性拮抗作用，但对 kainate 或 quisqualate 无此作用。苯环己哌啶、氯胺酮、SKF 10,047以及MK - 801的对映体作为N - Me - D - Asp拮抗剂时的效力与其作为[3H]MK - 801结合抑制剂的效力密切相关（r = 0.99）。这表明MK - 801结合位点与N - Me - D - Asp受体相关，并为MK - 801作为抗惊厥药的作用机制提供了解释。
