Journal article
Bias analyses of preclinical and clinical D2 dopamine ligands: studies with immediate and complex signaling pathways
The Journal of pharmacology and experimental therapeutics, Vol.352(3), pp.480-493
03/2015
DOI: 10.1124/jpet.114.220293
PMCID: PMC4352597
PMID: 25539635
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.
Details
- Title: Subtitle
- Bias analyses of preclinical and clinical D2 dopamine ligands: studies with immediate and complex signaling pathways
- Creators
- 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.)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.)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.)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.)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.) wattsv@purdue.edu
- Resource Type
- Journal article
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.352(3), pp.480-493
- Publisher
- United States
- DOI
- 10.1124/jpet.114.220293
- PMID
- 25539635
- PMCID
- PMC4352597
- ISSN
- 0022-3565
- eISSN
- 1521-0103
- Grant note
- S10-RR029274 / NCRR NIH HHS T32 GM067795 / NIGMS NIH HHS R01-MH060397 / NIMH NIH HHS R01 MH060397 / NIMH NIH HHS T32-GM067795 / NIGMS NIH HHS S10 RR029274 / NCRR NIH HHS
- Language
- English
- Date published
- 03/2015
- Academic Unit
- Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984065481002771
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