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 journalReview article (Academic Journal)peer-review

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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 languageEnglish
Pages (from-to)947-959
Number of pages13
JournalTrends in Pharmacological Sciences
Volume41
Issue number12
Early online date20 Oct 2020
DOIs
Publication statusPublished - 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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