Drug Abuse: Discovering Ligands for Pertinent GPCRs

描述(由申请人提供)： 国家药物滥用问题研究所(NIDA)的一个重要目标是促进开发新的药物成瘾治疗和预防方法。我们的中心将推进这一目标，为NIDA和NIH的研究人员提供有利的资源，以加快他们的成瘾研究的进展，包括但不限于发现和表征新型小分子化合物。我们计划的主要焦点是以孤儿和已鉴定的七个跨膜G蛋白偶联受体(GPCRs)以及烟碱型乙酰胆碱受体为代表的基因家族。在过去的四年里，在NIDA杜克P30中心的支持下，我们已经建立和维护了一个包含几乎所有与人类成瘾相关的GPCR的开放阅读框架的cDNA集合，更重要的是，我们已经建立了一个扩展的基于现成细胞的GPCR靶分析存储库，用于NIDA资助的科学家感兴趣的GPCR靶。我们的努力与NIH/NIDA的化学家和生物学家在其他多个机构进行了合作，包括与分子图书馆探针生产中心网络(MLPCN)的多个项目，结果发现了KOR、GPRS33、55和神经降压素1受体的新探针化合物。为了继续我们为药物成瘾提供药物治疗的使命，并将我们的运作维持在目前的水平，我们正在寻求作为NIDA P30卓越中心的续期资金，这将使我们的中心保持在药物成瘾研究的前沿。我们工作的主要范围将包括使用成瘾模型识别和在细胞内和体内表征新型工具化合物。我们的具体目标仍然是开发、维护和提供受体cDNA和细胞分析文库，供NID/VNIH调查人员立即访问，以及时(几天到几周内周转)筛选我们的合作者提供的受体靶标，对照我们或那些科学家提供的有限文库(1000-5,000种化合物)进行筛选；并建立旨在发现和表征针对成瘾行为的新型化合物的合作项目，包括将促进这些发现的新方法和技术。这一战略将加快 鉴定临床前化合物和工具化合物，以确定成瘾的生物学特征，并为药物发现技术方面的合作科学家提供教育资源。

DESCRIPTION (provided by applicant): An important goal of The National Institute on Drug Abuse (NIDA) is to foster the development of new approaches for drug addiction treatment and prevention. Our Center will advance this objective by providing an enabling resource for NIDA and NIH investigators for accelerating the progress of their addiction research, including but not limited to the discovery and characterization of novel small molecule compounds. The primary areas of focus of our program are the gene families represented by orphan and identified Seven Transmembrane G protein-coupled receptors (GPCRs) as well as nicotinic acetylcholine receptors. With NIDA support of our Duke P30 Center over, the past four years, we have established and maintained a cDNA collection containing the open reading frames for almost all human addiction associated GPCRs, and more importantly an expanding repository of off-the shelf cell-based assays for the GPCR targets of interest to NIDA funded scientists. Our efforts have produced collaborations with NIH/NIDA chemists and biologists at multiple other institutions, including multiple projects with the Molecular Libraries Probe Production Centers Network (MLPCN) that resulted in the discovery of novel probe compounds for the KOR, GPRs 33, 55, and the neurotensin 1 receptor. To continue our mission of providing a pharmacological treatment for drug addiction and maintaining our operation at current levels, we are seeking a renewal of funding as a NIDA P30 Center of Excellence that will enable our Center to remain at the forefront of drug addiction research. The primary scope of our work would include the identification and in cellulo and in vivo characterization of novel tool compounds using addiction models. Our specific aims remain, to develop, maintain, and provide receptor cDNA and cell assay libraries, for immediate access by NID/VNIH investigators, to screen in a timely manner (days to weeks turnaround) the receptor targets provided by our collaborators against limited libraries (1000-5,000 compounds) provided by us or those scientists; and establish collaborative projects aimed towards the discovery and characterization of novel compounds targeting addictive behaviors including the new assays and technologies that will facilitate those discoveries. This strategy will expedite the identification of preclinical compounds as well as tool compounds to characterize the biology of addiction and provide an educational resource for collaborating scientists in drug discovery technology.