MOLECULAR STUDIES OF MUSCARINIC RECEPTOR SUBTYPES

描述：(申请者摘要)乙酰胆碱能调节多种 中枢神经系统和全身的反应通过 毒鼠碱受体。M受体的五个亚型，属于 G蛋白偶联受体家族已经通过 分子生物学研究。尽管人们对生物化学的了解很多 以及由M受体引起或阻止的生理反应 配体，对激动剂之间的相互作用知之甚少 以及分子水平上具有M受体亚型的拮抗剂。 这些信息对于开发选择性配体的努力至关重要。 治疗阿尔茨海默病等神经系统疾病。 本提案侧重于了解配体之间的相互作用。 在分子水平上具有M受体亚型。分子 将使用建模和计算化学方法来开发 用于对接研究的M受体亚型模型。 生化研究将检查结合亲和力和激动剂 细胞内表达的M受体亚型配体的活性 台词。分子生物学方法将被用来产生受体 通过点突变进一步研究配体与Key的相互作用 M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上，目的是探索分子 对配体结合和活性很重要的特征。数量结构 活性研究将有助于确定分子特征 配体的活性，为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。 M受体对配体亲和力和激动剂活性的重要作用 子类型。这些研究将有助于产生新的化合物和 提高了对M受体亚型的选择性，并有助于 治疗阿尔茨海默病的新型配体的开发和应用 其他神经系统疾病。

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.