DEVELOPMENT OF NOVEL MUSCARINIC AGONISTS

新型毒蕈碱激动剂的开发

• 批准号: 2904490
• 负责人: WILLIAM S MESSER
• 金额: $ 17.64万
• 依托单位: UNIVERSITY OF TOLEDO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-08 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2904490
• 关键词: Alzheimer's disease; behavior test; brain disorder chemotherapy; chemical structure function; chemical synthesis; cholinergic agents; clone cells; dementia; drug design /synthesis /production; drug screening /evaluation; laboratory rat; ligands; memory disorders; methylphenyltetrahydropyridine; muscarinic receptor; nonhuman therapy evaluation; pharmacokinetics; receptor binding; thiazoles; tissue /cell culture

DESCRIPTION:(Applicant's Abstract) The neurotransmitter acetylcholine mediates a variety of responses within the central nervous system and plays an important role in memory function and cognition. Cholinergic cells within the basal forebrain denerate in Alzheimer's disease, a disorder associated with memory dysfunction and progressive cognitive decline. Research efforts have focused on developing selective M1 muscarinic agonists for the treatment of Alzheimer's disease. Over the past few years, several putative M1 agonists have been identified. The proposal focuses on the design, synthesis, and biological testing of novel compounds as selective muscarinic ligands. Chemical synthesis focuses on exploring a radically new approach to the development of muscarinic agonists, based on a novel series of bis-thiadiazole derivatives that display very high potency and activity at M1 receptors. Structure activity and molecular modeling studies will help identify the molecular features that contribute to activity and provide a basis for the rational design and synthesis of new ligands. In addition to pharmacological characterization of new compounds, biological studies will compare the affinity and efficiacy of several putative slective M1 muscarinic agonists at muscarinic receptors expressed in cultured cell lines and in the brain. Further studies will examine the ability of a few active and slective compounds to penetrate into the brain and reverse memory deficits associated with lesions of the septohippocampal cholinergic system. The overall goals of the project are to identify ligands with improved selectivity for muscarinic receptor subtypes, thereby providing important new pharmacological tools. A compound with high M1 agonists activity and the ability to penetrate into the brain also could become a drug candidate for the treatment of Alzheimer's disease. These studies will help determine the therapeutic utility of selective muscarinic agonists in the treatment of Alzheimer's disease. In addition the research could provide new approaches to the synthesis of compounds useful in a variety of neurological disorders.

描述：(申请人摘要) 神经递质乙酰胆碱在体内介导多种反应 中枢神经系统，在记忆功能和 认知力。阿尔茨海默病患者基底前脑胆碱能细胞变性 疾病，一种与记忆功能障碍和进行性疾病相关的疾病 认知能力下降。研究工作的重点是开发选择性的M1 用于治疗阿尔茨海默病的毒鼠碱激动剂。在过去的几年里 几年来，已经确定了几种假定的M1激动剂。该提案将重点放在 关于新型化合物AS的设计、合成和生物测试 选择性毒扁豆碱配体。化学合成专注于探索一种 开发M受体激动剂的全新方法，基于 新型系列双噻二唑衍生物，显示出非常高的效力和 M1受体的活性。结构活性与分子模拟研究 将有助于确定有助于活性和 为新配体的合理设计和合成提供了依据。 除了新化合物的药理学特征外，生物 研究将比较几种假定的选择M1的亲和力和效率 在培养细胞系中表达的M受体上的M受体激动剂 在大脑里。进一步的研究将检验几个活跃的和 选择性化合物渗透到大脑并逆转记忆缺陷 与隔海马胆碱能系统的损害有关。整体而言 该项目的目标是确定具有更好的选择性的配体 M受体亚型，从而提供了重要的新药理作用 工具。一种具有高M1激动剂活性和渗透能力的化合物 也可能成为治疗脑部疾病的候选药物 阿尔茨海默氏症。这些研究将有助于确定其治疗效用。 用于治疗阿尔茨海默病的选择性毒扁豆碱激动剂。在……里面 此外，这项研究还可以为合成有机化合物提供新的途径。 在各种神经疾病中有用的化合物。