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）乙酰胆碱介导多种 中枢神经系统和全身的反应， 毒蕈碱受体 毒蕈碱受体的五种亚型，属于 G蛋白偶联受体家族，已经通过 分子生物学研究 尽管我们对生物化学的了解很多， 和由毒蕈碱受体引起或阻止的生理反应 配体，关于激动剂的相互作用相对知之甚少 以及在分子水平上具有毒蕈碱受体亚型的拮抗剂。 这样的信息对于开发用于免疫球蛋白的选择性配体的努力是至关重要的。 治疗神经系统疾病，如阿尔茨海默病。 本提案的重点是了解配体的相互作用 与毒蕈碱受体亚型的关系 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。 生物化学研究将检查结合亲和力和激动剂 配体对细胞中表达的毒蕈碱受体亚型的活性 线 分子生物学方法将用于产生受体 用点突变进一步研究配体与关键的 毒蕈碱受体亚型上的氨基酸残基。 化学合成 将集中在几个关键化合物，目的是探索分子 对配体结合和活性重要的特征。 定量构 活性研究将有助于确定分子特征， 为配体活性的合理设计和合成提供依据 新的配体。 拟议研究的总体目标是确定分子特征 对配体亲和力和对毒蕈碱受体激动剂活性重要 亚型。 这些研究将有助于产生新的化合物， 改善对毒蕈碱受体亚型的选择性， 用于治疗阿尔茨海默病的新配体的开发， 其他神经系统疾病。