Advertisement

The Utilization of Mu-Opioid Receptor Biased Agonists: Oliceridine, an Opioid Analgesic with Reduced Adverse Effects

  • Ivan UritsEmail author
  • Omar Viswanath
  • Vwaire Orhurhu
  • Kyle Gress
  • Karina Charipova
  • Alan D. Kaye
  • Anh Ngo
Hot Topics in Pain and Headache (N. Rosen, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Hot Topics in Pain and Headache

Abstract

Purpose of Review

The purpose of this review is to summarize the current understanding of opioid pathways in mediating and/or modulating analgesia and adverse effects. Oliceridine is highlighted as a novel mu-opioid receptor agonist with selective activation of G protein and β-arrestin signaling pathways.

Recent Findings

Oliceridine (TRV130; [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine) is a novel MOR agonist that selectively activates G protein and β-arrestin signaling pathways. A growing body of evidence suggests that compared to existing MOR agonists, Oliceridine and other G protein-selective modulators may produce therapeutic analgesic effects with reduced adverse effects.

Summary

Oliceridine provides analgesic benefits of a pure opioid agonist while limiting related adverse effects mediated through the β-arrestin pathway. Recent insights into the function and structure of G protein-coupled receptors has led to the development of novel analgesic therapies.

Keywords

Oliceridine TRV130 G protein-coupled receptors (GPCR) Partial opioid agonists 

Notes

Compliance with Ethical Standards

Conflict of Interest

Ivan Urits, Omar Viswanath, Vwaire Orhurhu, Kyle Gress, Karina Charipova, and Anh Ngo declare no conflict of interest. Alan D. Kaye serves on the Speakers Bureau of Depomed and Merck.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Koblish M, Carr R, Siuda ER, Rominger DH, Gowen-MacDonald W, Cowan CL, et al. TRV0109101, a G protein-biased agonist of the μ -opioid receptor, does not promote opioid-induced mechanical allodynia following chronic administration. J Pharmacol Exp Ther. 2017;362:254–62.CrossRefGoogle Scholar
  2. 2.
    DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, et al. A G protein-biased ligand at the -opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013;344:708–17.CrossRefGoogle Scholar
  3. 3.
    •• Altarifii A, David B, Muchhala K, Blough B, Akbarali H, Negus S. Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (Oliceridine) on measures of antinociception, gastrointestinal function & abuse liability in rodents. J Psychopharacol. 2017;31:730–9 Study which assess safety and efficacy of Oliceridine.CrossRefGoogle Scholar
  4. 4.
    •• Fossler MJ, Sadler BM, Farrell C, Burt DA, Pitsiu M, Skobieranda F, et al. Oliceridine (TRV130), a novel G protein-biased ligand at the mu-opioid receptor, demonstrates a predictable relationship between plasma concentrations and pain relief. I: development of a pharmacokinetic/pharmacodynamic model. J Clin Pharmacol. 2018;58(6):750–61 A pharmacologic study of Oliceridine assigning a pharmacokinetic and pharmacodynamic model.CrossRefGoogle Scholar
  5. 5.
    Dhawan BN, et al. International Union of Pharmacology classification of opioid receptorsa. Am Soc Pharmacol Exp Ther. 1996;48:568–86.Google Scholar
  6. 6.
    Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors. Nat Rev Mol Cell Biol. 2002;3:639–50.CrossRefGoogle Scholar
  7. 7.
    Qian B, Soyer OS, Neubig RR, Goldstein RA. Depicting a protein’s two faces: GPCR classification by phylogenetic tree-based HMMs. FEBS Lett. 2003;554:95–9.CrossRefGoogle Scholar
  8. 8.
    Schneider S, Provasi D, Filizola M. How oliceridine (TRV-130) binds and stabilizes a μ-opioid receptor conformational state that selectively triggers G protein signaling pathways. Biochemistry. 2016;55:6456–66.CrossRefGoogle Scholar
  9. 9.
    Jacob J, Michaud G, Tremblay E. Mixed agonist-antagonist opiates and physical dependence. Br J Clin Pharmacol. 1979;7:291S–6S.CrossRefGoogle Scholar
  10. 10.
    Nasser AF, Heidbreder C, Liu Y, Fudala PJ. Pharmacokinetics of sublingual buprenorphine and naloxone in subjects with mild to severe hepatic impairment (child-Pugh classes a, B, and C), in hepatitis C virus-seropositive subjects, and in healthy volunteers. Clin Pharmacokinet Springer International Publishing. 2015;54:837–49.CrossRefGoogle Scholar
  11. 11.
    Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signalling and behaviour. Anesthesiology. 2011;115:1363–81.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Traynor J. μ-Opioid receptors and regulators of G protein signaling (RGS) proteins: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend. 2011;121:173–80.CrossRefGoogle Scholar
  13. 13.
    Stone LS, Molliver DC. In search of analgesia: emerging poles of GPCRs in pain. Mol Interv. 2009;9:234–51.CrossRefGoogle Scholar
  14. 14.
    •• Soergel DG, Subach RA, Burnham N, Lark MW, James IE, Sadler BM, et al. Biased agonism of the l-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. Pain. International Association for the Study of Pain. 2014;155:1829–35 A comparitive study of Oliceridine to morphine to assess for analgesic efficacy.Google Scholar
  15. 15.
    Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature Nature Publishing Group. 2016;537:185–90.CrossRefGoogle Scholar
  16. 16.
    Bohn LM, Gainetdinov RR, Sotnikova TD, Medvedev IO, Lefkowitz RJ, Dykstra LA, et al. Enhanced rewarding properties of morphine, but not cocaine, in beta(arrestin)-2 knock-out mice. J Neurosci. 2003;23:10265–73.CrossRefGoogle Scholar
  17. 17.
    Raehal KM, Walker JKL, Bohn LM. Morphine side effects in beta-arrestin-2 knockout mice. J Pharmacol Exp Ther. 2005;314:1195–201.CrossRefGoogle Scholar
  18. 18.
    Kang M, Maguma HT, Smith TH, Ross GR, Dewey WL, Akbarali HI. The role of -arrestin2 in the mechanism of morphine tolerance in the mouse and guinea pig gastrointestinal tract. J Pharmacol Exp Ther. 2012;340:567–76.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ivan Urits
    • 1
    Email author
  • Omar Viswanath
    • 2
    • 3
    • 4
  • Vwaire Orhurhu
    • 1
  • Kyle Gress
    • 5
  • Karina Charipova
    • 5
  • Alan D. Kaye
    • 6
  • Anh Ngo
    • 1
  1. 1.Beth Israel Deaconess Medical Center, Department of Anesthesia, Critical Care, and Pain MedicineHarvard Medical SchoolBostonUSA
  2. 2.Valley Anesthesiology and Pain ConsultantsPhoenixUSA
  3. 3.University of Arizona College of Medicine-PhoenixPhoenixUSA
  4. 4.Creighton University School of MedicineOmahaUSA
  5. 5.Georgetown University School of MedicineWashington, DCUSA
  6. 6.Department of AnesthesiologyLouisiana State University Health Sciences CenterNew OrleansUSA

Personalised recommendations