Ca2+-Dependent Block by Mematine and Selective Inhibition of Overactive NMDA Receptors

项目摘要/摘要 这里提出的研究涉及抑制N-甲基-D-天冬氨酸受体(NMDAR)的药物， 它们是在大多数脊椎动物兴奋性突触中发现的4亚单位离子型谷氨酸受体。NMDAR是 涉及一系列神经系统生理学和神经系统疾病。CA2流入 通过NMDARs是整个大脑突触可塑性的核心重要信号。过量的NMDAR- 然而，介导的钙内流与许多神经系统疾病有关，包括阿尔茨海默氏症 疾病和其他神经退行性疾病、中风和创伤性脑损伤。因此，看起来 NMDAR抑制剂应该具有广泛的治疗潜力。然而，大多数NMDAR抑制剂都是 临床试验不成功，可能是因为对NMDAR的广泛抑制有多个不可接受的 副作用。然而，美金刚是一种NMDAR通道阻断拮抗剂，是为数不多的药物之一 被批准用于治疗阿尔茨海默病。美金刚既有效又异常好的原因是- 是否可以容忍仍在争论之中。最近的观察提出了一种解释，即美金刚的作用是 稳定NMDAR的钙依赖脱敏状态，同时阻断NMDAR通道。结果, 美金刚优先抑制暴露在高细胞内钙浓度下的NMDAR，这是 NMDAR最有可能介导病理性钙内流。因此，设计的药物，如美金刚，抑制 随着细胞内钙的升高，NMDAR更有效地提供了一种前景看好的新策略，尤其是 有效的治疗剂。拟议研究的目标是加深对相互作用的理解 在美金刚和NMDAR之间，包括由三种不同类型的亚基组成的NMDAR，这三种亚基 都是通过挑战学习来广泛表达的。美金刚和其他通道在NMDAR上的结合位点 将使用先进的计算化学模型组合来识别和区分阻滞剂 以及野生型和突变型NMDARs的生理研究。在计算模型的指导下，新化合物 旨在以强烈依赖钙的方式与NMDAR交互作用的合成将用于深化 了解通道阻滞剂与NMDAR的相互作用。钙拮抗剂对细胞内钙的抑制作用 美金刚和其他通道阻滞剂将使用神经元准备进行检查，以及对钙的依赖 对它们的神经保护特性进行了评估。对细胞内依赖性增强的新型通道阻滞剂 CA2将成为未来开发更有效的阿尔茨海默病治疗方法的先导化合物 以及相关的神经退行性疾病。

PROJECT SUMMARY/ABSTRACT The research proposed here addresses drugs that inhibit N-methyl-D-aspartate receptors (NMDARs), which are 4-subunit ionotropic glutamate receptors found at most vertebrate excitatory synapses. NMDARs are involved in a remarkable range of both nervous system physiology and nervous system disorders. Ca2+ influx through NMDARs is a signal of central importance to synaptic plasticity throughout the brain. Excessive NMDAR- mediated Ca2+ influx, however, has been linked to many nervous system disorders, including Alzheimer's disease and other neurodegenerative diseases, stroke, and traumatic brain injury. It therefore would appear that NMDAR inhibitors should have wide therapeutic potential. However, most NMDAR inhibitors have been unsuccessful in clinical trials, probably because widespread inhibition of NMDARs has multiple unacceptable side effects. Memantine, however, is an NMDAR channel blocking antagonist that is one of the few drugs approved for treatment of Alzheimer's disease. The reasons why memantine is both effective and unusually well- tolerated remain under debate. An explanation is suggested by the recent observation that memantine acts to stabilizes a Ca2+-dependent desensitized state of NMDARs while blocking the NMDAR channel. As a result, memantine preferentially inhibits NMDARs that are exposed to high intracellular Ca2+ concentrations, which are the NMDARs most likely to mediate pathological Ca2+ influx. Thus, designing drugs that, like memantine, inhibit NMDARs more effectively as intracellular Ca2+ rises offers a promising new strategy for developing especially effective therapeutic agents. The goals of the proposed research are to deepen understanding of interactions between memantine and NMDARs, including of NMDARs composed of three different types of subunits, which are widely expressed by challenging to study. Binding sites on NMDARs for memantine and other channel blockers will be identified and distinguished using an advanced combination of computational chemical modeling and physiological study of wild-type and mutant NMDARs. Guided by computational models, new compounds designed to interact with NMDARs in a strongly Ca2+-dependent manner will be synthesized and used to deepen understanding of channel blocker-NMDAR interactions. The dependence on intracellular Ca2+ of inhibition by memantine and other channel blockers will be examined using neuronal preparations, and the Ca2+ dependence of their neuroprotective properties evaluated. New channel blockers with enhanced dependence on intracellular Ca2+ will serve as lead compounds for future development of more effective treatments for Alzheimer's disease and related neurodegenerative diseases.