Design of Small Molecules Acting at Regulators of G Protein Signaling

描述（由申请人提供）：鸟嘌呤核苷酸结合蛋白（G蛋白）的信号转导是阿片类药物、大麻素和多巴胺调节剂（可卡因和安非他明）等滥用药物功能的核心。一个新的蛋白质家族，G蛋白信号调节因子- RGS蛋白，通过抑制G蛋白参与这些药物滥用的行为强烈抑制信号传导。特别是RGS9基因敲除小鼠对安非他明、可卡因和吗啡的反应显著增强。RGS蛋白化学调节剂的发现将有助于我们进一步了解RGS蛋白在药物滥用中的生理和药理作用。这种RGS调节剂将验证RGS蛋白作为药物作用新靶点的潜力，并可能提供化合物作为治疗方法的先导。

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.