PARTIAL AGONISM AND MODULATION OF GABA RECEPTOR FUNCTION

描述(摘自申请人摘要)：变构调节剂， 它们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，可以有明显的 作为治疗剂的优点，包括高选择性和大容量 安全边际。在许多受体中观察到了调制 系统，最好的特征是GABA A受体(GABA AR)， 它受苯二氮卓类药物、巴比妥酸盐、类固醇和 某些金属阳离子。不幸的是，人们并没有很好地理解调制， 而缺乏受体调节的理论模型是一种 调制器合理设计的障碍。 这个项目的总体目标是了解 药物可以调节感受器功能，从而建立一种声音 为合理设计变构调节器提供了理论依据。 为此，一种受体调节的数学理论已经被提出 发展起来的。这项提案旨在使用GABA AR来测试这一理论 作为一个模范系统。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 取决于所使用的特定激动剂的疗效。为了测试 该模型将描述一系列GABA AR激动剂的特征 电生理学上的相对效力和效力，以及 GABA AR调节剂对激动剂剂量-反应曲线的影响 与模型的预测进行了比较。 除了对理论模型的肯定或否定，这些 预计研究将产生关于GABA AR激动剂的新数据 功效。受体的常规药理学方法 定性，主要依赖于效力的差异， 在很大程度上不足以应对GABA AR的多样性 中枢神经系统中的亚型。很可能是激动剂 药效将对受体的细微差异高度敏感 结构。因此，这项提议的第二个目标是开发一种 更有效的GABA AR药理表征策略 亚型，通过利用激动剂疗效的差异以及 威力。预计这一一般方法将广泛应用于 适用于其他神经递质受体的研究。 中枢神经系统。

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.