PARTIAL AGONISM AND MODULATION OF GABA RECEPTOR FUNCTION

GABA 受体功能的部分激动和调节

• 批准号: 2460671
• 负责人: TERRELL T GIBBS
• 金额: $ 18.12万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2460671
• 关键词: GABA receptor; barbiturates; benzodiazepines; cations; mathematical model; model design /development; neuropharmacology; neurotransmitter agonist; protein isoforms; protein structure function; receptor binding; receptor expression; steroids; tissue /cell culture; transfection

DESCRIPTION (taken from Applicant's Abstract): Allosteric modulators, which act by modulating the effects of endogenous agonists rather than by directly activating or blocking receptors, can have distinct advantages as therapeutic agents, including high selectivity and large safety margins. Modulation has been observed in a number of receptor systems, the best characterized being the GABA A receptor (GABA AR), which is modulated by benzodiazepines, barbiturates, steroids, and certain metal cations. Unfortunately, modulation is not well understood, and the lack of a theoretical model of receptor modulation is an obstacle to rational design of modulators. The overall goal of this project is to understand the mechanisms whereby drugs can modulate receptor function, and thereby to establish a sound theoretical basis for the rational design of allosteric modulators. Toward this end, a mathematical theory of receptor modulation has been developed. This proposal aims to test that theory, using the GABA AR as a model system. An important prediction of the model is that the effects of a modulator upon the agonist dose-response relationship will be dependent upon the efficacy of the particular agonist used. To test the model, a series of GABA AR agonists will be characterized electrophysiologically as to relative efficacy and potency, and the effects of GABA AR modulators upon agonist dose-response curves will be compared to the predictions of the model. In addition to confirming or rejecting the theoretical model, these studies are expected to yield novel data regarding GABA AR agonist efficacy. Conventional pharmacological methods of receptor characterization, which rely principally upon differences in potency, have been largely inadequate to deal with the multiplicity of GABA AR subtypes in the central nervous system. It is likely that agonist efficacy will be highly sensitive to subtle differences in receptor structure. A second goal of this proposal is therefore to develop a more powerful strategy for pharmacological characterization of GABA AR subtypes, by exploiting differences in agonist efficacy as well as potency. It is anticipated that this general approach will be broadly applicable to the study of other neurotransmitter receptors in the central nervous system.

说明书（摘自申请人的摘要）：变构调节剂， 其通过调节内源性激动剂的作用而不是 通过直接激活或阻断受体， 作为治疗剂的优点，包括高选择性和大 安全边际。 已经在许多受体中观察到调节作用， 系统，最好的特点是GABA A受体（GABA AR）， 其由苯二氮卓类、巴比妥类、类固醇调节， 某些金属阳离子 不幸的是，调制并没有得到很好的理解， 缺乏受体调节的理论模型是 阻碍了调制器的合理设计。 本项目的总体目标是了解 药物可以调节受体功能，从而建立一个健全的 变构调节剂的合理设计的理论基础。 为此，受体调节的数学理论已经被提出。 开发 这项提案旨在测试这一理论，使用GABA AR 作为一个模型系统。 该模型的一个重要预测是， 调节剂对激动剂剂量-反应关系的影响将 取决于所用的特定激动剂的效力。 测试 该模型，一系列GABA AR激动剂将被表征 电生理学上的相对功效和效力，以及 GABA AR调节剂对激动剂剂量-反应曲线的影响将是 与模型的预测相比。 除了确认或拒绝理论模型， 研究预计将产生关于GABA AR激动剂的新数据 功效受体的常规药理学方法 表征，其主要依赖于效力的差异， 在很大程度上不足以处理GABA AR的多样性， 中枢神经系统的亚型。 很可能激动剂 功效将对受体中细微差异高度敏感 结构 因此，本建议的第二个目标是制定一个 更强大的GABA AR药理学表征策略 亚型，通过利用激动剂功效的差异以及 力量 预计这一总体办法将广泛适用于 适用于其他神经递质受体的研究， 中枢神经系统