RESPONSES OF SUBPOPULATIONS OF MUSCARINIC RECEPTORS

毒蕈碱受体亚群的反应

• 批准号: 3115768
• 负责人: JOHN ELLIS
• 金额: $ 8.91万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-02-01 至 1988-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3115768
• 关键词: alkylation; anticholinergic agent; bioassay; brain cell; cell population study; chromatography; cognition disorders; ligands; neural information processing; neurochemistry; phosphorylation; radioassay; stimulus /response; tissue /cell culture

Reduced cholinergic function in the central nervous system contributes to memory disturbances, including those associated with senile dementia of the Alzheimer type. Previous studies by ourselves and others have demonstrated conclusively that distinct subtypes of muscarinic receptors are present in varying proportions in different brain regions. Classical receptor theory dictates that the most useful receptor classification schemes be based on the affinities of antagonists. The only antagonist that displays heterogeneous binding profiles and has been extensively characterized in response assays is pirenzipine; therefore, there is some reason for concern that the results obtained may reflect anomalous properties of this single compound, rather than an underlying pharmacology. Further, the characterizations may have been confounded by tissue-related differences, as the different responses were studied in different tissues. This proposal intends to correlate sophisticated assays of binding and response in model in vitro systems so as to relate the responses to given subpopulations. One line of investigation will evaluate multiple muscarinic responses and receptor binding in parallel, in identical preparations (neurally derived cell lines); thereby, the problems of between-tissue differences will be eliminated and the affinities of a given antagonist in the different response assays and binding assays can be compared directly. A second approach will examine a single response in regions of the brain that possess very different distributions of subpopulations, as a test of the uniformity of the relationship between response and receptor subtype. In both of these approaches, receptor subtypes will be defined according to the affinities of pirenzipine and other antagonists (e.g. gallamine, clozapine), characterized in our ongoing evaluation of potentially selective muscarinic ligands. Furthermore, the results of classical pharmacological methods, such as Schild analysis of competitive antagonists, will be supplemented by an independent procedure: selective protection of given subpopulation(s) of receptors from irreversible blockade by alkylating antagonists. Selective protection is a powerful technique that can also be used to determine the relationships between the subpopulations defined by different selective ligands and to evaluate the response characteristics of agonist-defined subpopulations. It is expected that these studies will lead to the development of agents with greater selectivity toward muscarinic subpopulations and that this knowledge may foster the development of newer and safer approaches to the enhancement of cognitive performance.

中枢神经系统中胆碱能功能的降低有助于 记忆障碍，包括与老年痴呆相关的记忆障碍 阿尔茨海默氏症类型。 我们和其他人的先前研究已经证明 结论认为，毒蕈碱受体的不同亚型存在 在不同的大脑区域中的比例不同。 古典受体理论 决定最有用的受体分类方案是基于 对手的亲和力。 唯一显示的对手 异质结合曲线，并已广泛表征 反应测定是吡renzipine；因此，有一些关注的理由 获得的结果可能反映了该单一的异常特性 化合物，而不是基础药理学。 此外， 特征可能与组织相关的差异混淆， 随着不同的反应在不同的组织中进行了研究。 这 提案旨在将具有约束力和响应的复杂测定法相关联 在体外系统模型中，以将响应与给定的响应联系起来 亚群。 一条调查将评估多个 毒蕈碱反应和受体结合，并联相同 制剂（神经衍生的细胞系）；因此， 组织之间的差异将被消除和给定的亲和力 在不同响应测定和结合测定中的拮抗剂可以是 比较直接。 第二种方法将检查一个单一的回应 大脑的区域具有截然不同的分布 亚群，作为对关系统一性之间关系的测试 反应和受体亚型。 在这两种方法中，受体 亚型将根据吡啶氮平和 其他拮抗剂（例如Gallamine，氯氮平）在我们正在进行的 评估潜在的选择性毒蕈碱配体。 此外， 经典药理方法的结果，例如 竞争性对手将以独立的程序补充： 选择性保护受体的给定亚群免受 通过烷基化拮抗剂不可逆地阻断。 选择性保护是 强大的技术也可以用来确定关系 在不同选择配体定义的亚群之间和 评估激动剂定义的亚群的响应特征。 预计这些研究将导致代理的发展 对毒蕈碱亚群的选择性更大，这是 知识可能会促进新的和更安全的方法的发展 认知表现的增强。