Drug Abuse: Discovering Ligands for Pertinent GPCRs

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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.