DEVELOPMENT OF AMIDINES AS SELECTIVE MUSCARINIC AGONISTS

描述：神经递质乙酰胆碱介导多种 在中枢神经系统内的反应，并发挥着重要作用 在记忆功能和认知方面。脑内胆碱能细胞 阿尔茨海默病(AD)患者的基底核变性 与记忆功能障碍和进行性认知能力下降有关。 目前治疗阿尔茨海默病的方法包括全面治疗 通过增加流向大脑的血液或提高注意力的药物， 虽然更具体的战略侧重于提高 乙酰胆碱或直接模拟胆碱能受体。这个 申请者的研究努力集中在开发有选择性的 治疗阿尔茨海默病的M受体激动剂。他们已经确认了 几种具有良好生物活性的活性配体，可用作 用于开发新型、选择性和中心的先导化合物- 有效的毒鼠强激动剂。 这项提案描述了设计、合成和生物测试 作为选择性毒扁豆碱激动剂的新型含嘧啶化合物。 化学合成将集中在几种关键化合物上，目的是 在一系列措施中提高效力、选择性和中心活性 1，4，5，6-四氢嘧啶衍生物。生物检测将寻求 确定对M1具有最高亲和力和有效性的分子 M_1受体在培养细胞系和M_1中的表达 海马体中的受体。体内研究将检验这种能力 使活性化合物渗透到大脑中并逆转记忆 与隔海马胆碱能损伤相关的缺陷 系统。结构活性研究将有助于确定分子 有助于活动并为 合理设计和合成新的配体。该计划的总体目标 拟议的研究是为了鉴定一种具有生物活性的化合物 有理由进一步发展成为治疗癌症的候选药物 广告。

DESCRIPTION: The neurotransmitter acetylcholine mediates a variety of responses within the central nervous system and plays an important role in memory function and cognition. The cholinergic cells within the basal nucleus degenerate in Alzheimer's Disease (AD), a disorder that is associated with memory dysfunction and progressive cognitive decline. Current therapeutic approaches for AD include generalized treatments with agents that increase blood flow to the brain or enhance attention, while more specific strategies focus on increasing levels of acetylcholine or directly simulating cholinergic receptors. The applicants' research efforts have focused on developing selective muscarinic agonists for the treatment of AD. They have identified several active ligands with promising biological activity that serve as lead compounds for the development of novel, selective, and centrally- active muscarinic agonists. This proposal describes the design, synthesis, and biological testing of novel amidine-containing compounds as selective muscarinic agonists. Chemical synthesis will focus on a few key compounds with the aim of improving potency, selectivity and central activity in a series of 1,4,5,6-tetrahydropyrimidine derivatives. Biological testing will seek to identify the molecules with highest affinity and efficacy for m1 muscarinic receptors expressed in cultured cell lines and M1 muscarinic receptors in the hippocampus. In vivo studies will examine the ability for active compounds to penetrate into the brain and reverse memory deficits associated with lesions of the septohippocampal cholinergic system. Structure activity studies will help identify the molecular features which contribute to activity and provide a basis for the rational design and synthesis of new ligands. The overall goal of the proposed studies is to identify a compound with biological activity warranting further development as a drug candidate for the treatment of AD.