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

Alexander Gillis, Andrea Kliewer, Eamonn Kelly, Graeme Henderson, Macdonald J Christie^*, Stefan Schulz^*, Meritxell Canals^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article (Academic Journal) › peer-review

99 Citations (Scopus)

162 Downloads (Pure)

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.

Original language	English
Pages (from-to)	947-959
Number of pages	13
Journal	Trends in Pharmacological Sciences
Volume	41
Issue number	12
Early online date	20 Oct 2020
DOIs	https://doi.org/10.1016/j.tips.2020.09.009
Publication status	Published - 1 Dec 2020

Bibliographical note

The acceptance date for this record is provisional and based upon the month of publication for the article.

Keywords

μ-opioid receptor
β-arrestin
biased signaling/agonists
intrinsic efficacy

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10.1016/j.tips.2020.09.009

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Fentanyl Overdose Deaths: Underlying Mechanisms
Henderson, G. (Principal Investigator)
1/04/19 → 31/07/22
Project: Research
MICA:Defining G protein- and arrestin-dependent signalling pathways of biased DOPr agonists and the relevance to their in vivo effects
Kelly, E. P. (Principal Investigator)
1/08/16 → 31/10/19
Project: Research

Cite this

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title = "Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor",

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 = "μ-opioid receptor, β-arrestin, biased signaling/agonists, intrinsic efficacy",

author = "Alexander Gillis and Andrea Kliewer and Eamonn Kelly and Graeme Henderson and Christie, {Macdonald J} and Stefan Schulz and Meritxell Canals",

note = "The acceptance date for this record is provisional and based upon the month of publication for the article.",

year = "2020",

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doi = "10.1016/j.tips.2020.09.009",

language = "English",

volume = "41",

pages = "947--959",

journal = "Trends in Pharmacological Sciences",

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AU - Gillis, Alexander

AU - Kliewer, Andrea

AU - Kelly, Eamonn

AU - Henderson, Graeme

AU - Christie, Macdonald J

AU - Schulz, Stefan

AU - Canals, Meritxell

N1 - The acceptance date for this record is provisional and based upon the month of publication for the article.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

KW - μ-opioid receptor

KW - β-arrestin

KW - biased signaling/agonists

KW - intrinsic efficacy

U2 - 10.1016/j.tips.2020.09.009

DO - 10.1016/j.tips.2020.09.009

M3 - Review article (Academic Journal)

C2 - 33097283

SN - 0165-6147

VL - 41

SP - 947

EP - 959

JO - Trends in Pharmacological Sciences

JF - Trends in Pharmacological Sciences

IS - 12

ER -

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

Abstract

Bibliographical note

Keywords

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Projects

Fentanyl Overdose Deaths: Underlying Mechanisms

MICA:Defining G protein- and arrestin-dependent signalling pathways of biased DOPr agonists and the relevance to their in vivo effects

Cite this