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.
The number of individuals in the United States who are addicted to drugs has increased to the extent that drug abuse has significantly impacted the social and economic fabric of the nation. A Duke University Center of Excellence as a consequence of collaborative programs with NIDA scientists in the area of drug discovery will expedite the identification and characterization of novel compounds for creating new approaches to understand and treat drug addiction.
|Mackie, Duncan I; Al Mutairi, Fuad; Davis, Reema B et al. (2018) hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia. J Exp Med 215:2339-2353|
|Toth, Krisztian; Slosky, Lauren M; Pack, Thomas F et al. (2018) Ghrelin receptor antagonism of hyperlocomotion in cocaine-sensitized mice requires ?arrestin-2. Synapse 72:|
|Fakhouri, Lara; Cook, Christopher D; Al-Huniti, Mohammed H et al. (2017) Design, synthesis and biological evaluation of GPR55 agonists. Bioorg Med Chem 25:4355-4367|
|Snyder, Joshua C; Rochelle, Lauren K; Ray, Caroline et al. (2017) Inhibiting clathrin-mediated endocytosis of the leucine-rich G protein-coupled receptor-5 diminishes cell fitness. J Biol Chem 292:7208-7222|
|Ray, Caroline; Soderblom, Erik J; Bai, Yushi et al. (2017) Probing the Allosteric Role of the ?5 Subunit of ?3?4?5 Nicotinic Acetylcholine Receptors by Functionally Selective Modulators and Ligands. ACS Chem Biol 12:702-714|
|Le Gonidec, Sophie; Chaves-Almagro, Carline; Bai, Yushi et al. (2017) Protamine is an antagonist of apelin receptor, and its activity is reversed by heparin. FASEB J 31:2507-2519|
|Jean-Charles, P-Y; Snyder, J C; Shenoy, S K (2016) Chapter One - Ubiquitination and Deubiquitination of G Protein-Coupled Receptors. Prog Mol Biol Transl Sci 141:1-55|
|Meza-Aviña, Maria Elena; Lingerfelt, Mary A; Console-Bram, Linda M et al. (2016) Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones. Bioorg Med Chem Lett 26:1827-1830|
|Barak, Larry S; Bai, Yushi; Peterson, Sean et al. (2016) ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse. ACS Chem Biol 11:1880-90|
|Snyder, Joshua C; Pack, Thomas F; Rochelle, Lauren K et al. (2015) A rapid and affordable screening platform for membrane protein trafficking. BMC Biol 13:107|
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