Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor

Alexander Gillis; Andrea Kliewer; Eamonn Kelly; Graeme Henderson; Macdonald J Christie; Stefan Schulz; Meritxell Canals

doi:10.1016/j.tips.2020.09.009

Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor

Trends Pharmacol Sci. 2020 Dec;41(12):947-959. doi: 10.1016/j.tips.2020.09.009. Epub 2020 Oct 20.

Authors

Alexander Gillis¹, Andrea Kliewer², Eamonn Kelly³, Graeme Henderson³, Macdonald J Christie⁴, Stefan Schulz⁵, Meritxell Canals⁶

Affiliations

¹ Discipline of Pharmacology, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
² Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.
³ School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, UK.
⁴ Discipline of Pharmacology, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia. Electronic address: mac.christie@sydney.edu.au.
⁵ Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany. Electronic address: stefan.schulz@med.uni-jena.de.
⁶ Division of Physiology, Pharmacology, and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, UK. Electronic address: M.Canals@nottingham.ac.uk.

PMID: 33097283
DOI: 10.1016/j.tips.2020.09.009

Abstract

G protein-biased agonists of the μ-opioid receptor (MOPr) have been proposed as an improved class of opioid analgesics. Recent studies have been unable to reproduce the original experiments in the β-arrestin2-knockout mouse that led to this proposal, and alternative genetic models do not support the G protein-biased MOPr agonist hypothesis. Furthermore, assessment of putatively biased ligands has been confounded by several factors, including assay amplification. As such, the extent to which current lead compounds represent mechanistically novel, extremely G protein-biased agonists is in question, as is the underlying assumption that β-arrestin2 mediates deleterious opioid effects. Addressing these current challenges represents a pressing issue to successfully advance drug development at this receptor and improve upon current opioid analgesics.

Keywords: biased signaling/agonists; intrinsic efficacy; β-arrestin; μ-opioid receptor.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Analgesics, Opioid*
Animals
GTP-Binding Proteins / metabolism
Ligands
Mice
Receptors, Opioid, mu* / metabolism
beta-Arrestin 2 / metabolism

Substances

Analgesics, Opioid
Ligands
Receptors, Opioid, mu
beta-Arrestin 2
GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding