Strategies for developing k opioid receptor agonists for the treatment of pain with fewer side effects

Kelly F. Paton, Diana V. Atigari, Sophia Kaska, Thomas Prisinzano, Bronwyn M. Kivell

Research output: Contribution to journalReview articlepeer-review

24 Scopus citations

Abstract

There is significant need to find effective, nonaddictive pain medications. k Opioid receptor (KOPr) agonists have been studied for decades but have recently received increased attention because of their analgesic effects and lack of abuse potential. However, a range of side effects have limited the clinical development of these drugs. There are several strategies currently used to develop safer and more effective KOPr agonists. These strategies include identifying G-protein-biased agonists, developing peripherally restricted KOPr agonists without centrally mediated side effects, and developing mixed opioid agonists, which target multiple receptors at specific ratios to balance side-effect profiles and reduce tolerance. Here, we review the latest developments in research related to KOPr agonists for the treatment of pain. SIGNIFICANCE STATEMENT This review discusses strategies for developing safer k opioid receptor (KOPr) agonists with therapeutic potential for the treatment of pain. Although one strategy is to modify selective KOPr agonists to create peripherally restricted or G-protein-biased structures, another approach is to combine KOPr agonists with m, d, or nociceptin opioid receptor activation to obtain mixed opioid receptor agonists, therefore negating the adverse effects and retaining the therapeutic effect.

Original languageEnglish
Pages (from-to)332-348
Number of pages17
JournalJournal of Pharmacology and Experimental Therapeutics
Volume375
Issue number2
DOIs
StatePublished - Nov 1 2020

Bibliographical note

Funding Information:
This work was supported by the Health Research Council of New Zealand, B.M.K. [Grant 16/646] and National Institutes of Health National Institute on Drug Abuse [Grant RO1: DA018151] (to T.E.P.). K.F.P. and D.V.A. each received a doctoral scholarship from Victoria University of Wellington. 1K.F.P. and D.V.A. contributed equally to this work. https://doi.org/10.1124/jpet.120.000134.

Funding Information:
This work was supported by the Health Research Council of New Zealand, B.M.K. [Grant 16/646] and National Institutes of Health National Institute on Drug Abuse [Grant RO1: DA018151] (to T.E.P.). K.F.P. and D.V.A. each received a doctoral scholarship from Victoria University of Wellington.

Publisher Copyright:
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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