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.

项目概要/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 亚基离子型谷氨酸受体。 NMDAR 是 涉及一系列显着的神经系统生理学和神经系统疾病。 Ca2+内流 通过 NMDAR 的信号是对整个大脑的突触可塑性至关重要的信号。 NMDAR 过多- 然而，介导的 Ca2+ 流入与许多神经系统疾病有关，包括阿尔茨海默病 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 抑制剂已被 临床试验不成功，可能是因为NMDARs的广泛抑制有多个不可接受的地方 副作用。然而，美金刚是一种 NMDAR 通道阻断拮抗剂，是少数药物之一 被批准用于治疗阿尔茨海默病。美金刚既有效又异常良好的原因是： 容忍度仍存在争议。最近的观察提出了一种解释，即美金刚的作用是 稳定 NMDAR 的 Ca2+ 依赖性脱敏状态，同时阻断 NMDAR 通道。因此， 美金刚优先抑制暴露于高细胞内 Ca2+ 浓度的 NMDAR，这些 NMDAR 是 NMDAR 最有可能介导病理性 Ca2+ 内流。因此，设计药物，如美金刚，抑制 随着细胞内 Ca2+ 的增加，NMDAR 更有效，这为开发特别是 有效的治疗剂。拟议研究的目标是加深对相互作用的理解 美金刚和 NMDAR 之间，包括由三种不同类型的亚基组成的 NMDAR， 被广泛表达为学习具有挑战性。 NMDAR 上美金刚和其他通道的结合位点 将使用计算化学模型的高级组合来识别和区分阻断剂 野生型和突变型 NMDAR 的生理学研究。在计算模型的指导下，新化合物 旨在以强 Ca2+ 依赖性方式与 NMDAR 相互作用的设计将被合成并用于加深 了解通道阻断剂-NMDAR 相互作用。抑制作用对细胞内 Ca2+ 的依赖性 将使用神经元制剂检查美金刚和其他通道阻滞剂，以及 Ca2+ 依赖性 评估其神经保护特性。新型通道阻滞剂，增强细胞内依赖性 Ca2+ 将作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。