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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19MH082441-08
Application #
8664920
Study Section
Special Emphasis Panel (ZMH1-ERB-C (03))
Program Officer
Brady, Linda S
Project Start
2007-09-28
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
8
Fiscal Year
2014
Total Cost
$1,527,521
Indirect Cost
$228,750
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Che, Tao; Majumdar, Susruta; Zaidi, Saheem A et al. (2018) Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Cell 172:55-67.e15
Wang, Sheng; Che, Tao; Levit, Anat et al. (2018) Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature 555:269-273
Rose, Samuel J; Pack, Thomas F; Peterson, Sean M et al. (2018) Engineered D2R Variants Reveal the Balanced and Biased Contributions of G-Protein and ?-Arrestin to Dopamine-Dependent Functions. Neuropsychopharmacology 43:1164-1173
McCorvy, John D; Butler, Kyle V; Kelly, Brendan et al. (2018) Structure-inspired design of ?-arrestin-biased ligands for aminergic GPCRs. Nat Chem Biol 14:126-134
McCorvy, John D; Wacker, Daniel; Wang, Sheng et al. (2018) Structural determinants of 5-HT2B receptor activation and biased agonism. Nat Struct Mol Biol 25:787-796
Peng, Yao; McCorvy, John D; Harps√łe, Kasper et al. (2018) 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell 172:719-730.e14
Wacker, Daniel; Wang, Sheng; McCorvy, John D et al. (2017) Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell 168:377-389.e12
Wacker, Daniel; Stevens, Raymond C; Roth, Bryan L (2017) How Ligands Illuminate GPCR Molecular Pharmacology. Cell 170:414-427
Arnsten, Amy F T; Girgis, Ragy R; Gray, David L et al. (2017) Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. Biol Psychiatry 81:67-77
Pappas, Andrea L; Bey, Alexandra L; Wang, Xiaoming et al. (2017) Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers. JCI Insight 2:

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