DEVELOPMENT OF NOVEL MUSCARINIC AGONISTS

描述：（申请人摘要） 神经递质乙酰胆碱介导的各种反应内的 中枢神经系统，在记忆功能中起着重要作用， 认知.阿尔茨海默病患者基底前脑内胆碱能细胞的退化 疾病，一种与记忆功能障碍和进行性 认知能力下降研究工作的重点是开发选择性M1 用于治疗阿尔茨海默病的毒蕈碱激动剂。过去几 多年来，已经鉴定了几种推定的M1激动剂。提案重点 设计，合成，和生物测试的新化合物， 选择性毒蕈碱配体。化学合成的重点是探索一种 一种全新的方法来开发毒蕈碱激动剂，基于 本发明提供了一系列新的双噻二唑衍生物， M1受体的活性。结构活性和分子模拟研究 将有助于识别有助于活动的分子特征， 为新配体的合理设计和合成提供依据。 除了新化合物的药理学表征外， 研究将比较几种假定的选择性M1的亲和力和效率， 在培养的细胞系中表达的毒蕈碱受体的毒蕈碱激动剂 和大脑中。进一步的研究将检查一些活跃的和 选择性化合物渗透到大脑和逆转记忆缺陷 与隔海马胆碱能系统损伤有关。整体 该项目的目标是确定具有更高选择性的配体， 毒蕈碱受体亚型，从而提供重要的新的药理学 工具.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 老年痴呆症这些研究将有助于确定治疗效用 选择性毒蕈碱激动剂在阿尔茨海默病治疗中的应用。在 此外，该研究还可以为合成 可用于多种神经障碍的化合物。

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.