DEVELOPMENT OF AMIDINES AS SELECTIVE MUSCARINIC AGONISTS

脒作为选择性毒蕈碱激动剂的开发

• 批准号: 2269099
• 负责人: WILLIAM S MESSER
• 金额: $ 19.38万
• 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 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2269099
• 关键词: Alzheimer's disease; Animalia; acetylcholine; amidines; brain disorder chemotherapy; chemical structure function; chemical synthesis; drug design /synthesis /production; drug screening /evaluation; hippocampus; mental disorder chemotherapy; muscarinic receptor; nonhuman therapy evaluation; pyrimidines; receptor binding; tissue /cell culture

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.

描述：神经递质乙酰胆碱介导了多种 中枢神经系统内的反应并发挥重要作用 在记忆功能和认知中。 胆碱能细胞 基础核在阿尔茨海默氏病（AD）中退化，这种疾病是 与记忆功能障碍和渐进认知能力下降有关。 当前的AD治疗方法包括广义治疗 通过增加血液流向大脑或增强注意力的药物， 而更具体的策略则集中于提高水平 乙酰胆碱或直接模拟胆碱能受体。 这 申请人的研究工作重点是发展选择性 毒蕈碱激动剂治疗AD。 他们已经确定了 几种具有有希望的生物学活性的活性配体 用于开发新颖，选择性和中央的铅化合物 活跃的毒蕈碱激动剂。 该建议描述了的设计，合成和生物学测试 新颖的含酰胺氨基化合物作为选择性毒蕈碱激动剂。 化学合成将集中于一些关键化合物，目的 一系列的效力，选择性和中心活动提高 1,4,5,6-四氢嘧啶衍生物。 生物测试将寻求 鉴定具有最高亲和力和功效的分子 在培养的细胞系和M1毒蕈碱中表达的毒蕈碱受体 海马中的受体。 体内研究将检查能力 活跃化合物可以渗透到大脑中并反向内存 与Septohappocampal胆碱能病变相关的缺陷 系统。 结构活性研究将有助于鉴定分子 有助于活动并为 新配体的理性设计和合成。 总体目标 拟议的研究是确定具有生物活性的化合物 作为候选药物治疗的进一步发展 广告。