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Review
. 2019 Nov;96(5):542-549.
doi: 10.1124/mol.119.115956. Epub 2019 Jun 7.

A Biased View of μ-Opioid Receptors?

Alexandra E Conibear  1 , Eamonn Kelly  2
Affiliations
Review

A Biased View of μ-Opioid Receptors?

Alexandra E Conibear et al. Mol Pharmacol. 2019 Nov.

Abstract

The field of biased agonism has grown substantially in recent years and the μ-opioid receptor has been one of the most intensively studied receptor targets for developing biased agonists. Yet, despite extensive research efforts, the development of analgesics with reduced adverse effects remains a significant challenge. In this review we discuss the evidence to support the prevailing hypothesis that a G protein-biased agonist at the μ-opioid receptor would be an effective analgesic without the accompanying adverse effects associated with conventional μ-opioid agonists. We also assess the current status of established and novel μ-opioid-receptor ligands that are proposed to be biased ligands. SIGNIFICANCE STATEMENT: The idea that biased agonists at the μ-opioid receptor might provide a therapeutic advantage in terms of producing effective analgesia with fewer adverse effects has driven the design of novel G protein-biased agonists. However, is the desirability of G protein-biased agonists at μ-opioid receptor substantiated by what we know of the physiology and pharmacology of the receptor? Also, do any of the novel biased agonists live up to their initial promise? Here we address these issues by critically examining the evidence that G protein bias really is desirable and also by discussing whether the ligands so far developed are clearly biased in vitro and whether this produces responses in vivo that might be commensurate with such bias.

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Figures

Fig. 1.
Fig. 1.
Signaling of biased agonists. In most cases agonists regarded as nonbiased can efficiently activate both G protein- and arrestin-dependent signaling. Relative to this, biased agonists preferentially activate either G protein- or arrestin-dependent signaling as shown in bold arrows.
Fig. 2.
Fig. 2.
(A and B) Simulated concentration-response curves to four agonists (a–d) at a GPCR in two different cellular assays measuring coupling efficiency to either pathway 1 or pathway 2. Many would conclude by eye that the red and green agonists are G protein-biased compared with the black agonist. (C) However, when bias factors for the blue, red, and green agonists are quantified by calculating the log ratios of transduction coefficients [∆∆log(τ/KA)], as discussed in the text, none of the agonists are found to be G protein-biased relative to the black agonist, as all of the agonists have values of ∆∆log(τ/KA) approximate to 0, confirming the absence of any bias.
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