Efficacy and ligand bias at the μ‐opioid receptor

Abstract

In order to describe drug action at a GPCR, a full understanding of the pharmacological terms affinity, efficacy and potency is necessary. This is true whether comparing the ability of different agonists to produce a measurable response in a cell or tissue, or determining the relative ability of an agonist to activate a single receptor subtype and produce multiple responses. There is a great deal of interest in the μ-opioid receptor (MOP receptor) and the ligands that act at this GPCR not only because of the clinically important analgesic effects produced by MOP agonists but also because of their liability to induce adverse effects such as respiratory depression and dependence. Our understanding of the mechanisms underlying these effects, as well as the ability to develop new, more effective MOP receptor drugs, depends upon the accurate determination of the efficacy with which these ligands induce coupling of MOP receptors to downstream signalling events. In this review, which is written with the minimum of mathematical content, the basic meaning of terms including efficacy, intrinsic activity and intrinsic efficacy is discussed, along with their relevance to the field of MOP receptor pharmacology, and in particular in relation to biased agonism at this important GPCR. LINKED ARTICLESRecent reviews on aspects of efficacy can be found at:

NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum

“…Indeed, MOR has been shown to be capable of activating ERK1/2 in striatal neurons when stimulated by a different opioid agonist fentanyl in a manner dependent on GRK3/β-arrestin [41]. This example serves to reinforce the ligand dependent nature of opioid receptor signaling that is becoming an increasingly accepted model of GPCR signaling [43, 44]. Nevertheless, from the perspective of G protein mediated transmission downstream from MOR, Ras signaling to Akt-mTOR/GSK3β seems to be the dominant pathway regulated by NF1.…”

Activators of G Protein Signaling Exhibit Broad Functionality and Define a Distinct Core Signaling Triad

“…An extension of this hypothesis regarding direct coupling of a GPCR to GaGPR is that a GPCR may couple to GaGPR in a ligand-dependent, conformationally-selective manner analogous to ligand-bias as described for GPCR coupling to Gabg and b-arrestin, offering substantial flexibility for systems to adapt and respond to extracellular stimuli (Fig. 2C) (Brink et al, 2000;Gesty-Palmer and Luttrell, 2011;Blattermann et al, 2012;Kenakin, 2012;Pradhan et al, 2012;Reiter et al, 2012;Rivero et al, 2012;Ahn et al, 2013;DeWire et al, 2013;Katritch et al, 2013;Kelly, 2013;Kenakin and Christopoulos, 2013;Wehbi et al, 2013;Wootten et al, 2013). One might imagine that receptor coupling to these three distinct transducer elements would regulate different signaling pathways and/or the strength and duration of generated signals and offer additional opportunities to expand upon the concept of pathway targeted drugs.…”

Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance

“…β-arrestin binding leads to receptor internalization and activation of a distinct group of signaling proteins such as extracellular signal-regulated kinase (ERK1/2), which is well characterized in adrenergic receptors compared to opioid receptors (Lefkowitz and Shenoy, 2005, Shenoy and Lefkowitz, 2005, Drake et al, 2008). Recent studies have shown that some MOPr agonists such as fentanyl and [D-Ala 2 , N-MePhe 4 , Gly-ol]-enkephalin (DAMGO) have high efficacy to recruit β-arrestin and activate of G proteins, whereas other opioids such as morphine are biased toward G protein signaling (McPherson et al, 2010, Molinari et al, 2010, Kelly, 2013, Thompson et al, 2014). …”