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

Mematine 的 Ca2 依赖性阻断和过度活跃的 NMDA 受体的选择性抑制

• 批准号: 10410546
• 负责人: Jon W. Johnson
• 金额: $ 54.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410546
• 关键词: Acetylcholinesterase; Acetylcholinesterase Inhibitors; Activities of Daily Living; Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; American; Area; Binding; Binding Sites; Biological Assay; Brain; Cerebrovascular Disorders; Chemical Models; Clinical; Clinical Trials; Communication; Comprehension; Computer Models; Dementia with Lewy Bodies; Dependence; Development; Disease; Docking; Drug Addiction; Drug Design; Drug usage; Effectiveness; Epilepsy; Excitatory Synapse; Exhibits; Exposure to; FDA approved; Functional disorder; Future; Glutamate Receptor; Goals; Ketamine; Lead; Learning; Link; Mediating; Memantine; Memory; Methods; Modeling; Molecular Mechanisms of Action; Mutagenesis; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor A1; Nerve Degeneration; Nervous System Physiology; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Parkinson' s Dementia; Pathologic; Pathology; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Preparation; Process; Property; Recombinants; Research; Role; Safety; Signal Transduction; Site-Directed Mutagenesis; Slice; Stroke; Synaptic plasticity; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Traumatic Brain Injury; United States National Institutes of Health; Vascular Dementia; Work; antagonist; base; cell injury; channel blockers; cholinergic neuron; chronic pain; clinical efficacy; cognitive function; desensitization; design; drug development; drug modification; effective therapy; excitotoxicity; experimental study; improved; in silico; inhibitor; innovation; molecular dynamics; mutant; nerve supply; nervous system disorder; neuron loss; neuroprotection; novel strategies; novel therapeutic intervention; novel therapeutics; predictive modeling; programs; rational design; receptor; side effect; simulation; therapeutically effective; tool; vascular cognitive impairment and dementia

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.

项目总结/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， 其是在大多数脊椎动物兴奋性突触中发现的4-亚基离子型谷氨酸受体。NMDAR是 涉及神经系统生理学和神经系统疾病的一个显著范围。ca 2+内流 通过NMDARs传递的信号对整个大脑的突触可塑性至关重要。过量NMDAR- 然而，介导的Ca 2+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抑制剂已经被 在临床试验中不成功，可能是因为NMDAR的广泛抑制具有多种不可接受的 副作用.然而，美金刚胺是一种NMDAR通道阻断剂， 被批准用于治疗老年痴呆症为什么美金刚胺既有效又非常好- 容忍度仍在讨论中。最近的观察表明美金刚的作用是 稳定NMDAR的Ca 2+依赖性脱敏状态，同时阻断NMDAR通道。因此，在本发明中， 美金刚优先抑制暴露于高细胞内Ca 2+浓度的NMDAR， NMDAR最可能介导病理性Ca 2+内流。因此，设计药物，如美金刚， 随着细胞内Ca 2+升高，NMDAR更有效地提供了一种有前途的新策略， 有效的治疗剂。拟议研究的目标是加深对相互作用的理解 美金刚和NMDAR之间的差异，包括由三种不同类型的亚基组成的NMDAR， 普遍表现为对学习的挑战。NMDAR上美金刚和其他通道的结合位点 将使用先进的计算化学模型组合来识别和区分阻断剂 以及野生型和突变型NMDAR的生理学研究。在计算模型的指导下， 设计成以强烈的Ca 2+依赖性方式与NMDAR相互作用的药物将被合成并用于加深 了解通道阻滞剂-NMDAR相互作用。细胞内Ca ~（2+）依赖性 美金刚和其他通道阻滞剂将使用神经元制剂进行检查，并且Ca 2+依赖性 它们的神经保护特性。具有增强的细胞内依赖性的新通道阻断剂 Ca 2+将成为未来开发更有效治疗阿尔茨海默病的先导化合物 和相关的神经退行性疾病。