Strategies for Developing κ Opioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects.

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.
(Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)