MOLECULAR STUDIES OF MUSCARINIC RECEPTOR SUBTYPES

毒蕈碱受体亚型的分子研究

• 批准号: 2655535
• 负责人: WILLIAM S MESSER
• 金额: $ 15.72万
• 依托单位: UNIVERSITY OF TOLEDO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2655535
• 关键词: anticholinergic agent; cholinergic agents; cyclic AMP; lipid metabolism; muscarinic receptor; mutant; phosphatidylinositols; plasmids; receptor binding; tissue /cell culture

DESCRIPTION: (Applicant's Abstract) Acetylcholine mediates a variety of responses in the central nervous system and throughout the body via muscarinic receptors. Five subtypes of muscarinic receptors, belonging to the family of G-protein-coupled receptors, have been identified through molecular biological studies. Although much is known about the biochemical and physiological responses elicited or prevented by muscarinic receptor ligands, comparatively little is known regarding the interaction of agonists and antagonists with muscarinic receptor subtypes at the molecular level. Such information is vital for efforts to develop selective ligands for the treatment of neurological disorders such as Alzheimer's disease. The present proposal focuses on understanding the interaction of ligands with muscarinic receptor subtypes at the molecular level. Molecular modeling and computational chemical approaches will be used to develop models of muscarinic receptor subtypes for use in docking studies. Biochemical studies will examine the binding affinities and agonist activities of ligands at muscarinic receptor subtypes expressed in cell lines. Molecular biological approaches will be used to generate receptors with point mutations to examine further the interaction of ligands with key amino acid residues on muscarinic receptor subtypes. Chemical synthesis will focus on a few key compounds with the aim of exploring the molecular features important for ligand binding and activity. Quantitative structure activity studies will help identify the molecular features which contribute to ligand activity and provide a basis for the rational design and synthesis of new ligands. The overall goal of the proposed studies is to identify molecular features important for ligand affinity and agonist activity at muscarinic receptor subtypes. These studies will be helpful in generating new compounds with improved selectivity for muscarinic receptor subtypes, and aid in the development of novel ligands for the treatment of Alzheimer's disease and other neurological disorders.

描述：（申请人的摘要）乙酰胆碱介导了各种 中枢神经系统和整个身体的反应通过 毒蕈碱受体。 五个亚型的毒蕈碱受体，属于 G蛋白偶联受体的家族已通过 分子生物学研究。 虽然对生化知识知之甚少 以及由毒蕈碱受体引起或预防的生理反应 配体，关于激动剂的相互作用，知之甚少 和毒蕈碱受体亚型的拮抗剂在分子水平上。 此类信息对于为开发选择性配体的努力至关重要 治疗神经系统疾病，例如阿尔茨海默氏病。 目前的提案重点是理解配体的相互作用 分子水平的毒蕈碱受体亚型。 分子 建模和计算化学方法将用于开发 用于对接研究的毒蕈碱受体亚型的模型。 生化研究将检查结合亲和力和激动剂 在细胞中表达的毒蕈碱受体亚型中配体的活性 线。 分子生物学方法将用于产生受体 使用点突变以进一步研究配体与钥匙的相互作用 毒蕈碱受体亚型的氨基酸残基。 化学合成 将专注于一些关键化合物，目的是探索分子 特征对于配体结合和活性很重要。 定量结构 活动研究将有助于确定贡献的分子特征 进行配体活动，并为理性设计和合成提供基础 新配体。 拟议研究的总体目标是识别分子特征 对毒蕈碱受体的配体亲和力和激动剂活性很重要 亚型。 这些研究将有助于与 提高了毒蕈碱受体亚型的选择性，并有助于 开发新型配体用于治疗阿尔茨海默氏病和 其他神经系统疾病。