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Drug regulators of nitric oxide production as Alzheimer's disease therapeutics

作为阿尔茨海默病治疗药物的一氧化氮产生的药物调节剂

基本信息

批准号：
8518216
负责人：
Katherine E Conant
金额：
$ 38.61万
依托单位：
EPIGEN BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8518216
关键词：
3-nitrotyrosine Adrenergic Agents Affinity Alzheimer&apos s Disease Amyloid Animal Disease Models Apolipoprotein E Area Behavioral Biochemical Biological Assay Brain Brain Injuries Brain Ischemia CYP2D6 gene CYP3A4 gene Cell Survival Characteristics Cognition Consensus Copper Data Dendritic Spines Denervation Deposition Development Disease Progression Dopamine Enzymes Evaluation Hippocampus (Brain)Human Human Cloning Hydrogen Peroxide In Vitro Inflammation Inflammatory Inhibitory Concentration 50 Laboratories Lead Ligands Literature Liver Microsomes Measures Mediating Mediator of activation protein Memory Loss Morbidity - disease rate Neurodegenerative Disorders Neuroglia Neurons Nitric Oxide Nitric Oxide Synthase Oxidative Stress Performance Peroxonitrite Pharmaceutical Preparations Phase Phenotype Positioning Attribute Pre-Clinical Model Production Property Proteins Reactive Oxygen Species Research Serotonin Signaling Molecule Site Small Business Technology Transfer Research Stress Structure Structure-Activity Relationship Superoxides Testing Therapeutic Tissues Toxic effect Transgenic Mice Work adrenergic base brain cell cholinergic conditioned fear cytotoxicity design efficacy testing improved in vivo inhibitor/antagonist morris water maze mortality mouse model neuronal survival neuroprotection news nitrosative stress novel pharmacophore piperidine pre-clinical predictive modeling public health relevance sigma-1 receptor sigma-2 receptor small molecule stressor

项目摘要

DESCRIPTION (provided by applicant): Druggable regulators of nitric oxide production as new Alzheimer's disease therapeutics Summary: Nitrosative stress is a critical mediator of the onset and progression of Alzheimer's disease (AD): it precedes and is associated with neuritic dystrophy and dendritic spine loss, A¿/amyloid accumulation and deposition, cholinergic denervation and a memory loss phenotype in animal models of disease. Normally, nitric oxide (NO) is an important signaling molecule and the enzyme that produces it, nitric oxide synthase (NOS), regulates ApoE and its other protein partners via nitrosylation. Under pro-inflammatory conditions (e.g. AD), oxidative stress upregulates NOS. Excess NO combines with oxygen radicals forming the reactive nitrosylating species peroxynitrite, which in turn causes promiscuous dysregulation and indiscriminate damage. Because direct inhibition of NOS results in systemic toxicity, our unique strategy is to selectively reduce NO activity at sites of inflammation. This will be achieved by targeting Sigma- 1 receptors (S1R), because they become important regulators of NOS activity only under conditions of oxidative stress. Our hypothesis is that elevated brain NO levels can be lowered at inflammatory sites by drugs that promote S1R-mediated reductions in NOS activity. The path for discovery and proof-of-concept phases includes: A) synthesis of additional novel candidate molecules to impart the appropriate selectivity and drug-like characteristics to compounds that reduce NO levels and promote neuronal and/or glial cell survival in vitro under conditions of nitrosative stress; B) evaluate 1- of these leads in a transgenic mouse model of AD by measuring reductions in CNS A¿/amyloid burden, 3-nitrotyrosine levels and improvements in cognition. Novel high affinity S1R candidates (hits) have been identified in our preliminary work and now we seek to create leads with refined drug-like properties for testing our target and mechanism- based hypothesis for therapeutics designed to slow the progression of AD.

描述（由申请人提供）：作为新的阿尔茨海默病治疗剂的一氧化氮产生的可药用调节剂概述：亚硝化应激是阿尔茨海默病（AD）的发作和进展的关键介质：它在疾病的动物模型中先于神经炎性营养不良和树突棘缺失、A/淀粉样蛋白积累和沉积、胆碱能去神经支配和记忆丧失表型并与之相关。通常，一氧化氮（NO）是一种重要的信号分子，产生它的酶一氧化氮合酶（NOS）通过亚硝基化调节ApoE及其其他蛋白质伴侣。在促炎性条件下（例如AD），氧化应激上调NOS。过量的NO与氧自由基结合，形成反应性亚硝酰化物质过氧亚硝酸盐，这反过来又导致混杂的失调和不分青红皂白的损害。由于直接抑制NOS会导致全身毒性，因此我们的独特策略是选择性降低炎症部位的NO活性。这将通过靶向Sigma- 1受体（S1 R）来实现，因为它们仅在氧化应激条件下才成为NOS活性的重要调节剂。我们的假设是升高的脑NO水平可以通过促进S1 R介导的NOS活性降低的药物在炎症部位降低。发现和概念验证阶段的途径包括：A）合成额外的新候选分子，以赋予化合物适当的选择性和药物样特征，所述化合物在亚硝化应激条件下降低NO水平并促进体外神经元和/或神经胶质细胞存活; B）通过测量CNS A的减少来评估AD转基因小鼠模型中的这些先导物中的1个。/淀粉样蛋白负荷、3-硝基酪氨酸水平和认知改善。在我们的初步工作中已经鉴定了新的高亲和力S1 R候选物（命中物），现在我们寻求创建具有精细药物样性质的先导物，用于测试我们的靶点和基于机制的假说，用于设计用于减缓AD进展的治疗剂。