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 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.
|Zhu, Hu; Roth, Bryan L (2014) Silencing synapses with DREADDs. Neuron 82:723-5|
|Lee, Sang-Min; Kant, Andrew; Blake, Daniel et al. (2014) SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C. Neuropharmacology 86:145-54|
|Katritch, Vsevolod; Fenalti, Gustavo; Abola, Enrique E et al. (2014) Allosteric sodium in class A GPCR signaling. Trends Biochem Sci 39:233-44|
|Giguere, Patrick M; Kroeze, Wesley K; Roth, Bryan L (2014) Tuning up the right signal: chemical and genetic approaches to study GPCR functions. Curr Opin Cell Biol 27:51-5|
|White, Kate L; Scopton, Alex P; Rives, Marie-Laure et al. (2014) Identification of novel functionally selective *-opioid receptor scaffolds. Mol Pharmacol 85:83-90|
|Lee, Hyeong-Min; Giguere, Patrick M; Roth, Bryan L (2014) DREADDs: novel tools for drug discovery and development. Drug Discov Today 19:469-73|
|Daigle, Tanya L; Ferris, Mark J; Gainetdinov, Raul R et al. (2014) Selective deletion of GRK2 alters psychostimulant-induced behaviors and dopamine neurotransmission. Neuropsychopharmacology 39:2450-62|
|Lee, Sang-Min; Yang, Yang; Mailman, Richard B (2014) Dopamine D1 receptor signaling: does G?Q-phospholipase C actually play a role? J Pharmacol Exp Ther 351:9-17|
|Zhu, Hu; Pleil, Kristen E; Urban, Daniel J et al. (2014) Chemogenetic inactivation of ventral hippocampal glutamatergic neurons disrupts consolidation of contextual fear memory. Neuropsychopharmacology 39:1880-92|
|Wang, Chong; Wu, Huixian; Evron, Tama et al. (2014) Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun 5:4355|
Showing the most recent 10 out of 74 publications