Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

Abstract

Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.

Pharmacological Characterization of µ-Opioid Receptor Agonists with Biased G Protein or β-Arrestin Signaling, and Computational Study of Conformational Changes during Receptor Activation

“…Since in most studies reported in the introduction, β-arrestin 2 was used [19,[21][22][23]29], for easy comparison we decided to characterize this isoform, despite being the minority as compared to β-arrestin 1 in most cells, including neurons. The use of β-arrestin 2 is supported by its similarity in opioid receptor binding with β-arrestin 1 [37,50]. Very recently, Pedersen et al measured the recruitment of both arrestins 1 and 2 following the activation of MOP by various ligands, and similar results were obtained [43].…”

“…Some researchers consider that the distinction between desired analgesic effects and unwanted side effects may not be as simple as G protein-mediated vs. β-arrestin-mediated effects [35,36]. As a matter of fact, many compounds characterized by good therapeutic indexes are indeed MOP partial agonists, whose efficacy is likely attributable to low efficacy partial agonism rather than G protein-bias [20,21,27,[37][38][39].…”

“…Although our understanding of biased ligand utility may be revaluated in the future, there is presently great interest in the investigation of the action mechanisms of biased ligands at the opioid receptors [37]. In this scenario, we studied the interactions of MOP with G-protein and β-arrestin 2, by means of the bioluminescence resonance energy transfer (BRET) assay, which measures the energy transfer between Renilla luciferase (RLuc) linked to the MOP and Renilla green fluorescent protein (RGFP) linked to the signal transducer proteins (G-protein or β-arrestin 2).…”

Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery

“…They reported on opioid agonist/NK1 antagonist Tyr-[D-Lys-Phe-Phe-Asp]-Asn-D-Trp-Phe-D-Trp-Leu-Nle-NH 2 and opioid agonist/NK1 agonist Tyr-[D-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH 2 peptide hybrids with antinociceptive efficacy without inducing analgesic tolerance or constipation in mice after intraperitoneal administration. Research approaches to diminish opioid liabilities take advantage of the current concept of functional selectivity, with biased ligands (agonists and antagonists) as innovative opportunities for opioid pain therapy and use management, subjects reviewed in [12,[15][16][17] and explored in a research article [18].…”

“…They described a large number of structurally diverse biased agonists, with the focus on the understanding of the limitations and advantages both in vitro and in vivo that they can provide. Azevedo Neto et al [16] discussed the accumulated literature on the potential of biased MOR agonists for the development as safer analgesics. They presented the pharmacology of three G protein-biased MOR agonists, oliceridine (TRV130), very recently approved for pain treatment, and PZM21 and SR-17018, in relationship to that of morphine and fentanyl, and proposed that their improved safety profile could be likely attributable to low efficacy partial agonism rather than G protein-bias.…”