Parsons C G, Danysz W, Quack G
Department of Pharmacological Research, Merz and Co., Frankfurt am Main, Germany.
Neuropharmacology. 1999 Jun;38(6):735-67. doi: 10.1016/s0028-3908(99)00019-2.
N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in numerous CNS disorders ranging from acute neurodegeneration (e.g. stroke and trauma), chronic neurodegeneration (e.g. Parkinson's disease, Alzheimer's disease, Huntington's disease, ALS) to symptomatic treatment (e.g. epilepsy, Parkinson's disease, drug dependence, depression, anxiety and chronic pain). However, many NMDA receptor antagonists also produce highly undesirable side effects at doses within their putative therapeutic range. This has unfortunately led to the conclusion that NMDA receptor antagonism is not a valid therapeutic approach. However, memantine is clearly an uncompetitive NMDA receptor antagonist at therapeutic concentrations achieved in the treatment of dementia and is essentially devoid of such side effects at doses within the therapeutic range. This has been attributed to memantine's moderate potency and associated rapid, strongly voltage-dependent blocking kinetics. The aim of this review is to summarise preclinical data on memantine supporting its mechanism of action and promising profile in animal models of chronic neurodegenerative diseases. The ultimate purpose is to provide evidence that it is indeed possible to develop clinically well tolerated NMDA receptor antagonists, a fact reflected in the recent interest of several pharmaceutical companies in developing compounds with similar properties to memantine.
N-甲基-D-天冬氨酸（NMDA）受体拮抗剂在众多中枢神经系统疾病中具有治疗潜力，这些疾病范围广泛，从急性神经退行性变（如中风和创伤）、慢性神经退行性变（如帕金森病、阿尔茨海默病、亨廷顿病、肌萎缩侧索硬化症）到对症治疗（如癫痫、帕金森病、药物依赖、抑郁症、焦虑症和慢性疼痛）。然而，许多NMDA受体拮抗剂在其假定的治疗剂量范围内也会产生非常不良的副作用。不幸的是，这导致了这样一个结论，即NMDA受体拮抗作用不是一种有效的治疗方法。然而，美金刚在治疗痴呆症所达到的治疗浓度下显然是一种非竞争性NMDA受体拮抗剂，并且在治疗剂量范围内基本上没有此类副作用。这归因于美金刚的中等效力以及相关的快速、强烈电压依赖性阻断动力学。本综述的目的是总结关于美金刚的临床前数据，这些数据支持其作用机制以及在慢性神经退行性疾病动物模型中的良好前景。最终目的是提供证据表明，确实有可能开发出临床耐受性良好的NMDA受体拮抗剂，这一事实反映在几家制药公司最近对开发具有与美金刚相似特性的化合物的兴趣上。
