Design of Small Molecules Acting at Regulators of G Protein Signaling

描述（由申请人提供）：G蛋白信号传导的调节因子（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因子。gpcr是包括大多数滥用药物在内的大量临床使用药物的靶标，RGS蛋白活性通常会抑制其功能。RGS4在啮齿动物神经性疼痛模型中过度表达，滥用药物如阿片类药物和精神兴奋剂也会影响RGS蛋白的表达。抑制RGS蛋白可以产生组织特异性增强GPCR激动剂的功能，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。这种竞争性修订（补充）应用源于我们成功发现的具有体内活性的高效RGS4抑制剂。这是第一次成功的化学靶向RGS蛋白。本研究的具体目的是：1)通过RGS4基因敲除小鼠的研究，确定新型RGS4抑制剂的体内作用是否通过RGS4介导；2)确定我们的新型RGS4抑制剂是否可以增强目前疗效有限的阿片受体激动剂的镇痛作用。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。

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.