In classical pharmacology, an agonist activates a single linear signal transduction pathway, whereas an antagonist blocks the action of the agonist and possesses no intrinsic activity. A rapidly evolving idea is that a given receptor, through various ligand-induced functional conformations, can engage multiple modalities through interaction with different signaling partners. Hence, a given ligand can bind a receptor and act as an antagonist for one signaling pathway while serving as an agonist at another or vice versa. This property is established for a number of G protein-coupled receptors. Importantly, none of the drugs in clinical use today have been developed with these multiple signaling considerations in mind. Additionally, agonists and antagonists are rarely completely selective and, for a given receptor, may alter signaling by influencing various receptor-mediated processes such as interaction with G proteins, desensitization, internalization, down-regulation, and receptor-mediated scaffolding of non-G protein signaling components. The physiological relevance of these properties is not fully appreciated. Thus, identifying the FUNCTIONAL SELECTIVITY of compounds may help reveal not only distinct biological processes, but also specific functional outcomes. Currently, the relevance of functional selectivity to psychiatry is unknown. This is particularly important for atypical antipsychotics, where dopamine D2 receptor antagonism is essentially a prerequisite for all these drugs;however, their other intrinsic activities are obscure. The overall goal of the U19 is to elucidate signal transduction mechanisms that are essential for antipsychotic efficacy in various relevant animal models. This proposed supplement brings to the funded U19 the critical capability of creating novel compounds with unprecedented patterns of functional selectivity for elucidating the key signal transduction pathways essential for antipsychotic actions. The U19 investigators as a collaborative group will carry out ligand design and synthesis, comprehensive in vitro profiling, and in vivo behavioral profiling in a synergistic manner to discover novel and functionally selective antipsychotic drug candidates that are more effective in animal models compared to existing atypical antipsychotics.

Public Health Relevance

Understanding of the role of functional selectivity and the signal transduction pathways that are critical to antipsychotic actions will speed the discovery and development of safer and more effective new therapeutics for schizophrenia and other related psychiatric disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZMH1-ERB-F (03))
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Brady, Linda S
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Rose, Samuel J; Pack, Thomas F; Peterson, Sean M et al. (2017) Engineered D2R Variants Reveal the Balanced and Biased Contributions of G-Protein and ?-Arrestin to Dopamine-Dependent Functions. Neuropsychopharmacology :
Urs, Nikhil M; Peterson, Sean M; Caron, Marc G (2017) New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy. Biol Psychiatry 81:78-85
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
Wang, Sheng; Wacker, Daniel; Levit, Anat et al. (2017) D4 dopamine receptor high-resolution structures enable the discovery of selective agonists. Science 358:381-386
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
Pogorelov, Vladimir M; Rodriguiz, Ramona M; Cheng, Jianjun et al. (2017) 5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice. Neuropsychopharmacology 42:2163-2177
Lansu, Katherine; Karpiak, Joel; Liu, Jing et al. (2017) In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol 13:529-536
Urs, Nikhil M; Gee, Steven M; Pack, Thomas F et al. (2016) Distinct cortical and striatal actions of a ?-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proc Natl Acad Sci U S A 113:E8178-E8186
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

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