Drug Abuse: Discovering Ligands for Pertinent GPCRs

描述（由申请人提供）：本中心向国家药物滥用研究所（NIDA）提出申请的一个重要目标是促进开发药物成瘾治疗和预防的新方法。我们建议通过为NIDA研究人员提供一个有利的资源来促进这一战略，这可以加速他们的成瘾研究的进展，包括但不限于发现新的小分子化合物。我们计划的主要重点领域是以孤儿为代表的基因家族，并确定了七种跨膜G蛋白偶联受体（GPCR）。在过去三年中，在NIDA的支持下，我们建立了一个cDNA集合，其中包含几乎所有人类成瘾相关GPCR的开放阅读框架，更重要的是，为NIDA资助的科学家感兴趣的超过一半的GPCR靶点建立了一个扩展的现成细胞检测库，目标是快速进展到剩余的细胞检测。我们的努力，正式成为杜克大学分析中心（DUAC），已经与NIH/NIDA化学家和生物学家在多个其他机构，包括五个联合正在进行的项目，其中包括分子库探针生产中心网络（MLPCN）。为了继续我们的计划在目前的努力水平，我们正在寻求资金作为一个NIDA P30卓越中心四年。作为一个卓越的中心，DUAC将继续处于药物成瘾研究的前沿，这是使技术和协同合作与其他NIDA科学家的结果。我们工作的主要范围将包括新工具化合物的鉴定和在细胞内和体内表征。 我们的具体施舍包括：1）开发和维护受体cDNA和细胞测定库，特别是包含荧光β-抑制蛋白和NIDA GPCR靶点的库，供NIDA研究人员立即访问。2)根据我们或合作科学家提供的有限库（1- 5，000种化合物），在DUAC及时筛选受体靶点（周转天数至数周）。和3）建立旨在MLPCN的项目，以发现新的工具化合物。这种合作策略应加快识别工具化合物，以表征成瘾的生物学特征，并为药物发现技术的合作科学家提供教育资源。

DESCRIPTION (provided by applicant): An important goal of this Center application to the National Institute on Drug Abuse (NIDA) is to foster the development of new approaches for drug addiction treatment and prevention. We propose to facilitate this strategy by providing an enabling resource for NIDA investigators that could accelerate the progress of their addiction research, including but not limited to the discovery of novel small molecule compounds. The primary area of focus of our program is the gene families represented by orphan and identified Seven Transmembrane G protein-coupled receptors (GPCRs). With NIDA support over the past three years we have established 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 over half of the GPCR targets of interest to NIDA funded scientists, with a goal of quickly progressing to the remaining cell assays. Our efforts, formalized as the Duke University Assay Center (DUAC), have produced joint collaborations with NIH/NIDA chemists and biologists at multiple other institutions, including five joint ongoing projects that include the Molecular Libraries Probe Production Centers Network (MLPCN). To continue our program at the current level of effort we are seeking funding as a NIDA P30 Center of Excellence for four years. As a Center of Excellence the DUAC would continue to be at the forefront of drug addiction research as a consequence of enabling technology and synergizing collaborations with other NIDA scientists. The primary scope of our work would include the identification and in cellulo and in vivo characterization of novel tool compounds. Our specific alms entail: 1)Development and maintenance of receptor cDNA and cell assay libraries, particularly containing fluorescent beta-arrestins and NIDA GPCR targets, for immediately access by NIDA investigators. 2) Screening in a timely manner (days to weeks turnaround) of receptor targets at DUAC against limited libraries (1-5,000 compounds) provided by us or the collaborating scientists. And 3) Establish projects aimed towards the MLPCN for discovery of novel tool compounds This collaborative strategy should expedite the identification tool compounds to characterize the biology of addiction and provide an educational resource for collaborating scientists in drug discovery technology.