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多种 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。 胆碱能细胞内 阿尔茨海默氏病 (AD) 中的基底核退化，这种疾病 与记忆功能障碍和进行性认知能力下降有关。 目前 AD 的治疗方法包括综合治疗 使用增加大脑血流量或增强注意力的药物， 而更具体的策略则侧重于提高 乙酰胆碱或直接模拟胆碱能受体。 这 申请人的研究工作集中于开发选择性的 用于治疗 AD 的毒蕈碱激动剂。 他们已经确定 几种具有良好生物活性的活性配体 用于开发新型、选择性和集中的先导化合物 活性毒蕈碱激动剂。 该提案描述了以下物质的设计、合成和生物测试 作为选择性毒蕈碱激动剂的新型含脒化合物。 化学合成将重点关注一些关键化合物，目的是 提高一系列的效力、选择性和中心活性 1,4,5,6-四氢嘧啶衍生物。 生物测试将寻求 鉴定对 m1 具有最高亲和力和功效的分子 培养细胞系和 M1 毒蕈碱受体中表达的毒蕈碱受体 海马体中的受体。 体内研究将检验这种能力 让活性化合物渗透到大脑并逆转记忆 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识别分子 有助于活动并为活动提供基础的功能 合理设计和合成新配体。 该项目的总体目标是 拟议的研究是为了鉴定具有生物活性的化合物 值得进一步开发作为治疗的候选药物 广告。