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: 10835208
• 负责人: Jon W. Johnson
• 金额: $ 4.73万
• 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/10835208
• 关键词: Address; Alzheimer' s Disease; Binding Sites; Brain; Chemical Models; Clinical Trials; Computer Models; Dependence; Development; Drug Design; Excitatory Synapse; Exposure to; Future; Glutamate Receptor; Goals; Lead; Link; Mediating; Memantine; N-Methyl-D-Aspartate Receptors; Nervous System Physiology; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Pathologic; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Preparation; Probability; Property; Research; Signal Transduction; Stroke; Synaptic plasticity; Therapeutic; Therapeutic Agents; Traumatic Brain Injury; Work; antagonist; cell injury; channel blockers; desensitization; design; effective therapy; improved; inhibitor; mutant; nervous system disorder; neuroprotection; novel strategies; novel therapeutics; side effect; therapeutically effective

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/文摘

项目成果

Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease.

阿尔茨海默氏病的新美容类似物的设计，合成以及体外和体内表征。

• DOI: 10.1016/j.ejmech.2022.114354
• 发表时间: 2022-06-05
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Turcu AL;Companys-Alemany J;Phillips MB;Patel DS;Griñán-Ferré C;Loza MI;Brea JM;Pérez B;Soto D;Sureda FX;Kurnikova MG;Johnson JW;Pallàs M;Vázquez S
• 通讯作者: Vázquez S