Design of Small Molecules Acting at Regulators of G Protein Signaling

描述(由申请人提供)：通过鸟嘌呤核苷酸结合蛋白(G蛋白)进行的信号转导是阿片类药物、大麻类药物和多巴胺调节剂(可卡因和苯丙胺)等滥用药物功能的核心。一个新的蛋白质家族，G蛋白信号调节蛋白-RGS蛋白，通过抑制参与这些药物滥用行为的G蛋白来强烈地抑制信号传递。特别是，RGS9基因敲除小鼠对苯丙胺、可卡因和吗啡的反应显著增强。RGS蛋白化学调节剂的出现将加深我们对RGS蛋白在药物滥用作用中的生理和药理作用的理解。这种RGS调节剂将验证RGS蛋白作为新的药物作用靶点的潜力，并可能提供化合物作为治疗的先导。 我们最近为RGS/G1相互作用的调节剂设计了高通量筛选，并鉴定了两系列RGS4的微摩尔抑制剂。在本项目中，我们将：1)评估这些化合物抑制RGS的分子机制，并进一步高通量筛选RGS4和RGS9的其他抑制剂或激活剂；2)确定构效关系，定义药效团模型，并优化已识别化合物的体外效力、细胞活性和预测的药代动力学性质；3)在转基因细胞模型系统和脑片中检测这些化合物，并优化其生物活性结构。该项目将为针对RGS蛋白质的药物开发提供初步步骤和原则证明。RGS蛋白质是与药物滥用有关的信号的关键调节器。

DESCRIPTION (provided by applicant): Signal transduction via guanine nucleotide binding proteins (G proteins) is central to the function of drugs of abuse such as opioids, cannabinoids, and dopamine modulators (cocaine and amphetamine). A novel family of proteins, Regulators of G Protein Signaling - RGS Proteins, strongly suppresses signaling by inhibitory G proteins that are involved in the actions of these drugs of abuse. In particular RGS9 knock-out mice show dramatically enhanced responses to amphetamine, cocaine, and morphine. The availability of chemical modulators of RGS proteins will enhance our understanding of physiological and pharmacological roles of RGS proteins in the actions of drugs of abuse. Such RGS modulators will validate the potential of RGS proteins as a novel target of drug action and could provide compounds to serve as leads for therapeutics. We have recently devised high-throughput screens for modulators of the RGS/G1 interaction and identified two series of micromolar inhibitors of RGS4. In this project, we will: 1) evaluate the molecular mechanisms of RGS inhibition by these compound and undertake further high throughput screening for additional inhibitors or activators of RGS4 and RGS9, 2) determine structure-activity relations, define pharmacophore models, and optimize in vitro potency, cellular activity, and predicted pharmacokinetic properties of identified compounds, and 3) examine these compounds in transfected cell model systems and brain slices and optimize structures for biological activity. This project will provide the initial steps and proof of principle for medications development targeting RGS proteins - a key modulator of signaling related to drug abuse.