RESPONSES OF SUBPOPULATIONS OF MUSCARINIC RECEPTORS

毒蕈碱受体亚群的反应

• 批准号: 3115764
• 负责人: JOHN ELLIS
• 金额: $ 18.19万
• 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 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3115764
• 关键词: acetylcholine; allosteric site; brain stem; chimeric proteins; corpus striatum; dopamine; inhibitor /antagonist; laboratory mouse; muscarinic receptor; neurons; neuropharmacology; phosphatidylinositols; phosphorylation; protein structure function; receptor binding; receptor sensitivity; stimulant /agonist; tissue /cell culture; transfection

DESCRIPTION (Investigator's Abstract): The aim of this proposal is the discovery and classification of subtype selective allosteric agents that modulate muscarinic receptor functions in well-defined ways, with minimal competitive complications. Malfunctions of muscarinic cholinergic systems of the CNS are known or thought to be involved in many diseases, yet treatment with directly acting muscarinic agonists and antagonists has not proven generally beneficial to date. This may relate in part to the adverse effects of currently available muscarinic drugs. Indirectly acting (allosteric) drugs have some inherent advantages of efficacy and safety over directly acting (competitive) agents; the allosterically-acting benzodiazepines are good examples of CNS drugs that are very effective and safe. Studies of substances which allosterically modulate muscarinic receptors have been hampered by three problems: the drugs that have been investigated so far exert some competitive effects as well as allosteric effects; the specificity of these agents toward subtypes of muscarinic receptors has been difficult to determine in tissues where mixed subtypes are present; and, it has been possible to determine whether different modulators act at a single, well defined, allosteric site. Using assays that are not affected by concomitant competitive effects, it has been found that all cloned muscarinic receptor subtypes (m1-m5) are subject to allosteric regulation and that there are marked differences between subtypes. We has also been shown that two allosteric modulators interact in a way that strongly suggests that they bind to the same well-defined allosteric site on cardiac (m2) muscarinic receptors. The proposed studies aim to expand upon these findings. (1) We will screen a growing number of allosteric modulators to determine their subtype-specificities and whether they act at common site(s). (2) We will examine allosteric modulation of functional responses by novel paradigms that are not confound by concomitant competitive interactions. Studies of other allosterically-acting drugs have shown that allosteric modulators may antoagonize or augment responses, or may affect the rate of receptor desensitization. (3) Finally, we will construct chimeric receptors to identify the receptor sequences responsible for the allosteric effects.

描述（研究者的摘要）：该提议的目的是 亚型选择性变构剂的发现和分类 调节毒蕈碱受体以明确的方式起作用，而最小 竞争并发症。 毒蕈碱胆碱能系统的故障 中枢神经系统已知或认为与许多疾病有关 直接作用的毒蕈碱激动剂和拮抗剂的治疗尚未 迄今为止被证明是有益的。 这可能部分与 当前可用的毒蕈碱药物的不利影响。 间接行动 （变构）药物具有疗效和安全性的固有优势 过度直接表演（竞争性）代理；变构作用 苯二氮卓类是非常有效和 安全的。 对变构调节毒蕈碱的物质的研究 受体受到三个问题的阻碍： 到目前为止的调查发挥了一些竞争效果以及变构的作用 效果；这些药物对毒蕈碱的亚型的特异性 在混合亚型的组织中很难确定受体 在场；而且，有可能确定是否不同 调节器在一个单一的，定义明确的变构站点上起作用。 使用不受伴随竞争影响影响的测定法 已经发现所有克隆的毒蕈碱受体亚型（M1-M5）is 受到变构调节的约束，存在明显的差异 在亚型之间。 我们还显示了两个变构调节器 互动以强烈表明它们结合在一起的方式 心脏（M2）毒蕈碱受体上定义明确的变构部位。 这 拟议的研究旨在扩大这些发现。 （1）我们将筛选 越来越多的变构调节剂来确定其 亚型特异性及其是否在普通站点起作用。 （2）我们会的 通过新范式检查功能响应的变构调制 与竞争互动并不是混淆的。 研究 其他变构作用的药物表明，变构调节剂可能 反对或增强反应，或可能影响受体的速率 脱敏。 （3）最后，我们将构建嵌合受体 确定负责变构作用的受体序列。