Pharmacological Characters of Oliceridine, a μ-Opioid Receptor G-Protein–Biased Ligand in Mice

Liang, De‐Yong; Li, Wenwu; Nwaneshiudu, Chinwe A.; Irvine, Karen‐Amanda; Clark, J. David

doi:10.1213/ane.0000000000003662

Cited by 41 publications

(40 citation statements)

References 39 publications

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“…In earlier clinical trials, it produced opioid-like subjective effects in humans, suggesting abuse liability [ 36 ] consistent with recent reports in the literature on TRV130 in rodents shows mixed results with the drug showing constipation, addictive properties, and tolerance similar to classical MOR agonists in rodents while also showing less signs of somatic withdrawal, raising doubts about the drug’s safety profile [ 37 , 38 ]. However, with the recent FDA approval, the potential of G-biased agonism can now finally be tested in humans and findings may help the field to either call it a day on MOR biased agonsim or push for the development of additional biased agonists.…”

Section: Mor Biased Agonismsupporting

confidence: 74%

Biased Opioid Ligands

2020

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Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

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Section: Mor Biased Agonismsupporting

confidence: 74%

Biased Opioid Ligands

2020

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“…By contrast, morphine anti‐nociceptive tolerance is consistently found to be dependent on β‐arrestin2 recruitment (Bohn et al, 2000; Bull, Baptista‐Hon, Sneddon, et al, 2017; Kliewer et al, 2019; Yang et al, 2011). It is not surprising then that TRV130, which causes little recruitment of β‐arrestin2 in vitro, caused no anti‐nociceptive tolerance when administered daily to WT mice for 10 days, a finding consistent with previous reports (Altarifi et al, 2017; Liang et al, 2019). However, when administered under the same conditions to μ+/− mice, with 50% fewer receptors than WT mice (Matthes et al, 1996), TRV130 caused marked anti‐nociceptive tolerance after only 4 days.…”

Section: Discussionsupporting

confidence: 90%

“…We had anticipated that, given its low efficacy in the β‐arrestin2 recruitment assay, TRV130 would not exhibit anti‐nociceptive tolerance and in keeping with previous studies (Altarifi et al, 2017; Liang et al, 2019) this was true in the case of WT mice. However, robust tolerance occurred in μ+/− mice.…”

Section: Discussionsupporting

confidence: 56%

TRV130 partial agonism and capacity to induce anti‐nociceptive tolerance revealed through reducing available μ‐opioid receptor number

Singleton

Baptista‐Hon

Edelsten

et al. 2021

British J Pharmacology

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Background and Purpose: β-Arrestin2 recruitment to μ-receptors may contribute to the development of opioid side effects. This possibility led to the development of TRV130 and PZM21, opioids reportedly biased against β-arrestin2 recruitment in favour of G-protein signalling. However, low efficacy β-arrestin2 recruitment by TRV130 and PZM21 may simply reflect partial agonism overlooked due to overexpression of μ-receptors. Experimental Approach: Efficacies and apparent potencies of DAMGO, morphine, PZM21 and TRV130 as stimulators of β-arrestin2 recruitment and inhibitors of cAMP accumulation were assessed in CHO cells stably expressing μ-receptors. Receptor availability was depleted through prior exposure of cells to the irreversible antagonist, β-FNA. We also examined whether μ-receptor availability influences TRV130 anti-nociception and/or tolerance using the tail withdrawal assay in wild-type C57BL/6 and μ+/− mice.

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“…In this study, the authors also demonstrated that the antinociceptive effects of oliceridine in the mouse sciatic nerve ligation model are associated with lower tolerance liability than fentanyl [ 36 ]. This latter finding was independently confirmed by a different group that compared the antinociceptive effects of morphine and oliceridine after a 4-day treatment with the mouse tail withdrawal assay [ 37 ]. Interestingly these authors also reported that mice treated chronically with oliceridine display, in response to an injection of naloxone, a withdrawal syndrome similar to that observed in morphine treated mice.…”

Section: Pharmacological Studies—are Mu-receptor Agonists Biased Tmentioning

confidence: 65%

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

et al. 2020

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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.

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Pharmacological Characters of Oliceridine, a μ-Opioid Receptor G-Protein–Biased Ligand in Mice

Abstract: Aside from reduced respiratory depression, G-protein[FIGURE DASH]biased agonists such as oliceridine may reduce opioid maladaptations and enhance the quality of surgical recovery.

Cited by 41 publications

References 39 publications

Biased Opioid Ligands

Biased Opioid Ligands

TRV130 partial agonism and capacity to induce anti‐nociceptive tolerance revealed through reducing available μ‐opioid receptor number

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

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