The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: Low-affinity, uncompetitive antagonism
The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: Low-affinity, uncompetitive antagonism
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DOI：
10.2174/1567205053585846
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发表时间：
2005-04-01
影响因子：
2.1
通讯作者：
Lipton, Stuart A.
中科院分区：
文献类型：
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作者：
Lipton, Stuart A.
在西方国家，阿尔茨海默病（AD）是最常见的痴呆症。事实上，如果不加限制，到本世纪中叶，照顾 AD 患者的经济成本可能会耗尽美国的全部国民生产总值。直到最近，治疗这种情况的唯一可用药物是胆碱能治疗，它可以在一定程度上对症状增强认知状态，但它们不具有神经保护作用。事实上，许多潜在的神经保护药物在临床试验中都失败了，因为它们的耐受性很差。然而，在我们发现其临床耐受的作用机制后，一种神经保护药物美金刚最近被欧盟和美国食品和药物管理局（FDA）批准用于治疗阿尔茨海默病。最近的 3 期临床试验表明，美金刚可有效治疗轻度和中度至重度阿尔茨海默病以及可能的血管性痴呆（多发梗塞性痴呆）。在这里，我们回顾了美金刚作用的分子机制，以及该药物用于治疗这些至少部分由兴奋性毒性介导的神经系统疾病的基础。兴奋性毒性被定义为过度暴露于神经递质谷氨酸或其膜受体的过度刺激，导致神经元损伤或死亡。兴奋毒性神经元细胞死亡部分是由 N-甲基-D-天冬氨酸 (NMDA) 型谷氨酸受体过度激活介导的，这会导致过量的 Ca2+ 通过受体相关离子通道流入。然而，生理性 NMDA 受体活性对于正常神经元功能也至关重要。这意味着阻断几乎所有 NMDA 受体活性的潜在神经保护剂很可能会产生不可接受的临床副作用。因此，许多先前的 NMDA 受体拮抗剂在针对多种神经退行性疾病的高级临床试验中都令人失望地失败了。相比之下，我们实验室的研究表明，金刚烷衍生物美金刚优先阻断过度的 NMDA 受体活性，而不破坏正常活性。美金刚通过其作为一种无竞争力、低亲和力、开放通道阻断剂的作用来实现这一点。当受体相关离子通道过度开放时，它会优先进入受体相关离子通道，最重要的是，它的解离速率相对较快，因此不会在通道中大量积累而干扰正常的突触传递。临床应用证实了美金刚具有良好耐受性的预测。除了阿尔茨海默氏病之外，美金刚目前正在针对其他神经系统疾病进行试验，包括其他形式的痴呆、抑郁症、青光眼和严重的神经性疼痛。一系列第二代美金刚衍生物目前正在开发中，可能被证明具有比美金刚更好的神经保护特性。这些第二代药物利用了 NMDA 受体除了其离子通道之外还有其他调节位点的事实，这些位点也可能用于安全但有效的临床干预。
In western countries, Alzheimer's disease (AD) is the most common form of dementia. In fact, if left uncurbed, the economic cost of caring for AD patients could consume the entire gross national product of the U.S.A. by the middle of this century. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. In fact, many potential neuroprotective drugs tested in clinical trials failed because they were poorly tolerated. However, after our discovery of its clinically-tolerated mechanism of action, one neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of both mild and moderate-to-severe Alzheimer's disease and possibly vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell death is mediated in part by overactivation of N-methyl-D-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca2+ influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Clinical use has corroborated the prediction that memantine is thus well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including other forms of dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-gene ration drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention.