title: Biased Agonism of Endogenous Opioid Peptides at the μ-Opioid Receptor.
abstract: 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.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.).
authors.forename: Georgina L
authors.initials: GL
authors.lastname: Thompson
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.).
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Coudrat
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.).
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.) meri.canals@monash.edu arthur.christopoulos@monash.edu.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (G.L.T., J.R.L., T.C., P.M.S., A.C., M.C.); and Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, Victoria, Australia (G.L.T.) meri.canals@monash.edu arthur.christopoulos@monash.edu.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Canals
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004723:Endorphins / Q000494:pharmacology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D018847:Opioid Peptides / Q000819:agonists*; D025341:Principal Component Analysis; D011498:Protein Precursors / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004723:Endorphins; D009842:Oligopeptides; D018847:Opioid Peptides; D011498:Protein Precursors; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C025681:alpha-neoendorphin; D019204:GTP-Binding Proteins