The overall goal of this project is to test the hypothesis that functionally-selective D2-dopamine receptor agonists with extreme signaling bias for the canonical and non-canonical signaling pathways will represent novel treatments for schizophrenia and related disorders. This U19 represents a collaboration between investigators at the University of North Carolina Chapel Hill, Duke University and Pfizer Pharmaceuticals. To achieve this overall goal we have the following three main projects: Project #1: Will deliver beta-arrestin-biased agonist clinical candidates of dopamine D2 receptors (D2R) for the treatment of schizophrenia and related disorders, and create novel D2R ligands with a wide range of unprecedented patterns of functional selectivity (including Gi-biased full and partial agonists) as chemical probes for elucidating the key signaling pathways essential for antipsychotic efficacy and side-effects. Project #2: Will provide novel animal models to validate compounds delivered in Project 1 in order to demonstrate functional selectivity in vivo. Project #3: Will provide ADMETsupport and additional in vivo and in vitro testing to support advancement of compounds identified in Projects 1 and 2 for proof-of-concept clinical trials The three interconnected and synergistic projects will be supported by three cores: 1. Administrative Core: which will provide administrative support for various teams of investigators and scheduling of Scientific Advisory Board meetings for periodic feedback. 2. Screening Core: which will provide all of the in vitro screening and profiling required to advance compounds. This core will be assisted by the National Institute of Mental Health Psychoactive Drug Screening Program at the University of North Carolina Chapel Hill Medical School. 3. Behavioral Core: will provide the essential in vivo validation required to demonstrate antipsychotic drug like activity as well as activity against bot positive and negative symptomatology using appropriate animal models.

Public Health Relevance

Public Relevance: Schizophrenia is an illness which affects at least 1% of the world's population. This project will lead to the creation, validation and ultimately proof-of-concept trials for novel medications for treating schizophrenia. Compounds developed may also have utility for schizophrenia-related disorders as well as bipolar disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Program--Cooperative Agreements (U19)
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Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-C (03))
Program Officer
Brady, Linda S
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Urs, Nikhil M; Gee, Steven M; Pack, Thomas F et al. (2016) Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proc Natl Acad Sci U S A 113:E8178-E8186
Chen, Xin; McCorvy, John D; Fischer, Matthew G et al. (2016) Discovery of G Protein-Biased D2 Dopamine Receptor Partial Agonists. J Med Chem 59:10601-10618
Urban, Daniel J; Zhu, Hu; Marcinkiewcz, Catherine A et al. (2016) Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons. Neuropsychopharmacology 41:1404-15
Butler, Kyle V; Bohn, Kelsey; Hrycyna, Christine A et al. (2016) Non-Substrate Based, Small Molecule Inhibitors of the Human Isoprenylcysteine Carboxyl Methyltransferase. Medchemcomm 7:1016-1021
Park, Su M; Chen, Meng; Schmerberg, Claire M et al. (2016) Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice. Neuropsychopharmacology 41:704-15
Roth, Bryan L (2016) DREADDs for Neuroscientists. Neuron 89:683-94
Farrell, Martilias S; McCorvy, John D; Huang, Xi-Ping et al. (2016) In Vitro and In Vivo Characterization of the Alkaloid Nuciferine. PLoS One 11:e0150602
Nocjar, C; Alex, K D; Sonneborn, A et al. (2015) Serotonin-2C and -2a receptor co-expression on cells in the rat medial prefrontal cortex. Neuroscience 297:22-37
Huang, Xi-Ping; Karpiak, Joel; Kroeze, Wesley K et al. (2015) Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 527:477-83
Kroeze, Wesley K; Sassano, Maria F; Huang, Xi-Ping et al. (2015) PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat Struct Mol Biol 22:362-9

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