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Research ArticleNeuropharmacology

Bias Analyses of Preclinical and Clinical D2 Dopamine Ligands: Studies with Immediate and Complex Signaling Pathways

Tarsis F. Brust, Michael P. Hayes, David L. Roman, Kevin D. Burris and Val J. Watts
Journal of Pharmacology and Experimental Therapeutics March 2015, 352 (3) 480-493; DOI: https://doi.org/10.1124/jpet.114.220293
Tarsis F. Brust
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana (T.F.B., V.J.W.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa (M.P.H., D.L.R.); and Quantitative Biology, Eli Lilly and Company, Indianapolis, Indiana (K.D.B.)
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Michael P. Hayes
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana (T.F.B., V.J.W.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa (M.P.H., D.L.R.); and Quantitative Biology, Eli Lilly and Company, Indianapolis, Indiana (K.D.B.)
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David L. Roman
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana (T.F.B., V.J.W.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa (M.P.H., D.L.R.); and Quantitative Biology, Eli Lilly and Company, Indianapolis, Indiana (K.D.B.)
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Kevin D. Burris
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana (T.F.B., V.J.W.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa (M.P.H., D.L.R.); and Quantitative Biology, Eli Lilly and Company, Indianapolis, Indiana (K.D.B.)
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Val J. Watts
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana (T.F.B., V.J.W.); Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa (M.P.H., D.L.R.); and Quantitative Biology, Eli Lilly and Company, Indianapolis, Indiana (K.D.B.)
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Abstract

G protein–coupled receptors (GPCRs) often activate multiple signaling pathways, and ligands may evoke functional responses through individual pathways. These unique responses provide opportunities for biased or functionally selective ligands to preferentially modulate one signaling pathway over another. Studies with several GPCRs have suggested that selective activation of signaling pathways downstream of a GPCR may lead to safer and more effective drug therapies. The dopamine D2 receptor (D2R) is one of the main drug targets in the therapies for Parkinson’s disease and schizophrenia. Recent studies suggest that selective modulation of individual signaling pathways downstream of the D2R may lead to safer antipsychotic drugs. In the present study, immediate effectors of the D2R (i.e., Gαi/o, Gβγ, β-arrestin recruitment) and more complex signaling pathways (i.e., extracellular signal-regulated kinase phosphorylation, heterologous sensitization, and dynamic mass redistribution) were examined in response to a series of D2R ligands. This was accomplished using Chinese hamster ovary cells stably expressing the human D2L dopamine receptor in the PathHunter β-Arrestin GPCR Assay Platform. The use of a uniform cellular background was designed to eliminate potential confounds associated with cell-to-cell variability, including expression levels of receptor as well as other components of signal transduction, including G protein subunits. Several well characterized and clinically relevant D2R ligands were evaluated across each signaling pathway in this cellular model. The most commonly used methods to measure ligand bias were compared. Functional selectivity analyses were also used as tools to explore the relative contribution of immediate D2R effectors for the activation of more complex signaling pathways.

Footnotes

    • Received October 11, 2014.
    • Accepted December 19, 2014.
  • This research was supported by the National Institutes of Health National Institute of Mental Health [Grant R01-MH060397]; the National Institutes of Health National Institute of General Medicine [Grant T32-GM067795]; the National Institutes of Health National Center for Research Resources [Grant S10-RR029274]; the American Foundation for Pharmaceutical Education; and the Purdue Research Foundation.

  • Portions of this work were presented previously as a poster presentation at the following conference: Brust TF, Hayes MP, Roman DL, and Watts VJ (2014) G protein contribution to complex signaling pathways downstream of the dopamine D2L receptor [FASEB J 28(Suppl):662.10]. Experimental Biology 2014; 2014 Apr 26–30; San Diego, CA.

  • dx.doi.org/10.1124/jpet.114.220293.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 352 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 3
1 Mar 2015
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Research ArticleNeuropharmacology

Ligand Bias for Immediate and Complex Effectors

Tarsis F. Brust, Michael P. Hayes, David L. Roman, Kevin D. Burris and Val J. Watts
Journal of Pharmacology and Experimental Therapeutics March 1, 2015, 352 (3) 480-493; DOI: https://doi.org/10.1124/jpet.114.220293

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Research ArticleNeuropharmacology

Ligand Bias for Immediate and Complex Effectors

Tarsis F. Brust, Michael P. Hayes, David L. Roman, Kevin D. Burris and Val J. Watts
Journal of Pharmacology and Experimental Therapeutics March 1, 2015, 352 (3) 480-493; DOI: https://doi.org/10.1124/jpet.114.220293
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