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Biased Agonism of Endogenous Opioid Peptides at the μ-Opioid Receptor

Thompson, Georgina L.; Lane, J. Robert; Coudrat, Thomas; Sexton, Patrick M.; Christopoulos, Arthur; Canals, Meritxell


Georgina L. Thompson

Associate Professor

Thomas Coudrat

Patrick M. Sexton

Arthur Christopoulos


Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. Biased agonism is having a major impact on modern drug discovery, and describes the ability of distinct G protein-coupled receptor (GPCR) ligands to activate different cell signaling pathways, and to result in different physiologic outcomes. To date, most studies of biased agonism have focused on synthetic molecules targeting various GPCRs; however, many of these receptors have multiple endogenous ligands, suggesting that "natural" bias may be an unappreciated feature of these GPCRs. The μ-opioid receptor (MOP) is activated by numerous endogenous opioid peptides, remains an attractive therapeutic target for the treatment of pain, and exhibits biased agonism in response to synthetic opiates. The aim of this study was to rigorously assess the potential for biased agonism in the actions of endogenous opioids at the MOP in a common cellular background, and compare these to the effects of the agonist D-Ala2-N-MePhe4-Gly-ol enkephalin (DAMGO). We investigated activation of G proteins, inhibition of cAMP production, extracellular signal-regulated kinase 1 and 2 phosphorylation, β-arrestin 1/2 recruitment, and MOP trafficking, and applied a novel analytical method to quantify biased agonism. Although many endogenous opioids displayed signaling profiles similar to that of DAMGO, α-neoendorphin, Met-enkephalin-Arg-Phe, and the putatively endogenous peptide endomorphin-1 displayed particularly distinct bias profiles. These may represent examples of natural bias if it can be shown that they have different signaling properties and physiologic effects in vivo compared with other endogenous opioids. Understanding how endogenous opioids control physiologic processes through biased agonism can reveal vital information required to enable the design of biased opioids with improved pharmacological profiles and treat diseases involving dysfunction of the endogenous opioid system.


Thompson, G. L., Lane, J. R., Coudrat, T., Sexton, P. M., Christopoulos, A., & Canals, M. (2015). Biased Agonism of Endogenous Opioid Peptides at the μ-Opioid Receptor. Molecular Pharmacology, 88(2), 335-346.

Journal Article Type Article
Acceptance Date May 26, 2015
Online Publication Date Jun 24, 2015
Publication Date 2015-08
Deposit Date Jan 17, 2020
Journal Molecular Pharmacology
Print ISSN 0026-895X
Electronic ISSN 1521-0111
Publisher American Society for Pharmacology and Experimental Therapeutics
Peer Reviewed Peer Reviewed
Volume 88
Issue 2
Pages 335-346
Keywords alpha-neoendorphin; endomorphin 1; endorphin; enkephalin[2 dextro alanine 4 methylphenylalanine 5 glycine]; guanine nucleotide binding protein; mu opiate receptor; oligopeptide; opiate peptide; protein precursor; agonists; animal; chemistry; CHO cell line
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