Abstract
There is significant need to find effective, nonaddictive pain medications. κ 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 κ 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 μ, δ, or nociceptin opioid receptor activation to obtain mixed opioid receptor agonists, therefore negating the adverse effects and retaining the therapeutic effect.
Footnotes
- Received May 28, 2020.
- Accepted August 27, 2020.
↵1 K.F.P. and D.V.A. contributed equally to this work.
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.
- Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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In this issue
Strategies for Developing Safer κ Opioid Receptor Agonists
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- Abstract
- Introduction
- κ Opioid Receptor Signaling and the Role in Pain
- Traditional Arylacetamide κ Opioid Receptor Agonists
- Strategies to Develop κ Opioid Receptor Agonists with Reduced Side Effects
- G-Protein–Biased κ Opioid Receptor Agonists
- Peripherally Restricted κ Opioid Receptor Agonists
- Mixed κ Opioid Receptor Agonists
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