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

描述(由申请人提供)：作为新的阿尔茨海默病疗法的一氧化氮产生的可药物调节剂摘要：亚硝化应激是阿尔茨海默病(AD)发生和发展的关键媒介：在疾病的动物模型中，它先于神经性营养不良和树突棘丢失，A？/淀粉样蛋白积累和沉积，胆碱能去神经和记忆丧失表型，并与之相关。正常情况下，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)，通过亚硝化来调节ApoE和其他蛋白质伙伴。在促炎条件下(如阿尔茨海默病)，氧化应激可上调一氧化氮合酶。过量的NO与氧自由基结合形成活性亚硝基物种过氧亚硝酸盐，进而导致混杂失调和不分青红皂白的损害。由于直接抑制一氧化氮合酶会导致全身毒性，我们的独特策略是选择性地减少炎症部位的一氧化氮活性。这将通过靶向Sigma-1受体(S1R)实现，因为它们只有在氧化应激条件下才成为一氧化氮合酶活性的重要调节因子。我们的假设是，炎症部位升高的脑NO水平可以通过促进S1R介导的NOS活性降低的药物来降低。发现和验证概念阶段的途径包括：a)合成其他新的候选分子，以赋予化合物适当的选择性和药物样特性，这些化合物可降低NO水平并促进神经元和/或神经胶质细胞在亚硝化应激条件下的体外存活；b)在AD转基因小鼠模型中，通过测量CNS A/淀粉样蛋白负担、3-硝基酪氨酸水平和认知改善来评估这些线索中的1种。在我们的初步工作中已经发现了新的高亲和力S1R候选者(HITS)，现在我们寻求创造具有精炼药物样属性的线索，以测试我们的靶向和基于机制的假说，旨在减缓AD的进展。

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.