Design of Small Molecules Acting at Regulators of G Protein Signaling

描述（由申请人提供）：G蛋白信号传导调节剂（RGS蛋白）是通过G蛋白偶联受体（GPCR）家族进行信号传导的关键调节剂。GPCR是大量临床使用的药物（包括大多数滥用药物）的靶标，并且RGS蛋白活性通常抑制其功能。在啮齿动物神经性疼痛模型中已经报道了RGS 4的过表达，并且滥用药物如阿片类药物和精神兴奋剂也影响RGS蛋白表达。抑制RGS蛋白可以产生GPCR激动剂功能的组织特异性增强，具有提高其特异性和减少副作用的潜力。该项目的长期目标是发现RGS蛋白活性的小分子化学调节剂-抑制或增强其功能。这项竞争性修订（补充）申请源于我们成功发现了具有体内活性的高效RGS 4抑制剂。这代表了RGS蛋白的第一次成功的化学靶向。本研究的具体目的是：1）通过在RGS 4敲除小鼠中的研究确定新RGS 4抑制剂的体内作用是否通过RGS 4介导，2）确定我们的新型RGS 4抑制剂是否可以增强目前疗效有限的δ-阿片激动剂的镇痛作用。这些研究将为这种通过化学靶向RGS蛋白来改善药物治疗的新方法提供原理证明。 与公共卫生的关系：麻醉性镇痛药，包括吗啡和海洛因，是主要的滥用药物。它们对控制疼痛很重要，它们的作用在细胞内由一种新发现的机制调节。我们刚刚开发出这种机制的抑制剂，可以通过一类独特的阿片类药物来改善疼痛缓解，这种药物可能会降低滥用的可能性。

DESCRIPTION (provided by applicant): Regulators of G protein signaling (RGS proteins) are critical modulators of signaling through the G protein coupled receptor (GPCR) family. GPCRs are the targets of a significant number of clinically used drugs including most drugs of abuse and RGS protein activity generally suppresses their function. Overexpression of RGS4 has been reported in rodent neuropathic pain models and abused drugs such as opioids and psychostimulants also affect RGS protein expression. Inhibition of RGS proteins can produce tissue-specific enhancement of GPCR agonist function with the potential to improve their specificity and reduce side-effects. The long term goals of this project are to discover small molecule chemical modulators of RGS protein activity - either to inhibit or enhance their function. This competitive revision (supplement) application takes off from our successful discovery of highly potent RGS4 inhibitors that have activity in vivo. This represents the first successful chemical targeting of RGS proteins. The specific aims of the present study are to: 1) establish whether the in vivo actions of the new RGS4 inhibitors are mediated through RGS4 by studies in RGS4 knockout mice, 2) determine whether our novel RGS4 inhibitors can enhance the analgesic actions of delta-opioid agonists which currently have limited efficacy. These studies would provide proof-of-principle for this novel approach to improving pharmacotherapy by chemically targeting RGS proteins. PUBLIC HEALTH RELEVANCE: Narcotic analgesics, including morphine and heroin, are major drugs of abuse. They are important for control of pain and their actions are modulated inside the cell by a newly discovered mechanism. We have just developed inhibitors of that mechanism that could provide improved pain relief with a unique class of opiate drugs that may have decreased abuse potential.