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Design of Small Molecules Acting at Regulators of G Protein Signaling

作用于 G 蛋白信号传导调节器的小分子的设计

基本信息

批准号：
8117015
负责人：
RICHARD R NEUBIG
金额：
$ 30.41万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8117015
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Affinity Agonist Amphetamines Binding Sites Biological Biological Models Blood - brain barrier anatomy Brain Cannabinoids Cell model Cell physiology Cells Chemicals Cocaine Corpus striatum structure Development Docking Dopamine Drug Kinetics Drug abuse Drug effect disorder Family Flow Cytometry Fluorescence Resonance Energy Transfer G Protein-Coupled Receptor Signaling G-substrate GTP-Binding Protein Regulators GTP-Binding Proteins In Vitro Knockout Mice Ligands Link Methods Michigan Modeling Molecular Morphine Mutagenesis Opioid Permeability Pharmaceutical Preparations Physiological Property Protein Family RGS Proteins Rattus Regulation Role Series Signal Transduction Slice Structure Therapeutic United States National Institutes of Health Universities base design drug of abuse guanine nucleotide binding protein high throughput screening improved inhibitor/antagonist interest lead series novel pharmacophore receptor response small molecule small molecule libraries therapeutic development tool

项目摘要

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.

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、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，通过参与这些滥用药物的作用的抑制性G蛋白强烈抑制信号传导。特别是RGS 9基因敲除小鼠对安非他明、可卡因和吗啡的反应显着增强。RGS蛋白的化学调节剂的可用性将增强我们对RGS蛋白在滥用药物的作用中的生理和药理作用的理解。这样的RGS调节剂将验证RGS蛋白作为药物作用的新靶点的潜力，并且可以提供用作治疗剂的先导化合物。我们最近设计了RGS/G1相互作用调节剂的高通量筛选，并确定了两个系列的RGS 4微摩尔抑制剂。在这个项目中，我们将：1）评估这些化合物抑制RGS的分子机制，并对RGS 4和RGS 9的另外的抑制剂或激活剂进行进一步的高通量筛选，2）确定结构-活性关系，定义药效团模型，并优化鉴定的化合物的体外效力、细胞活性和预测的药代动力学性质，和3）在转染的细胞模型系统和脑切片中检查这些化合物，并优化生物活性的结构。该项目将提供针对RGS蛋白的药物开发的初步步骤和原理证明-RGS蛋白是与药物滥用相关的信号传导的关键调节剂。