Kappa opioid receptor (KOR) is a member of the opioid receptor system, the G protein-coupled receptors that are expressed throughout the peripheral and central nervous systems and play crucial roles in the modulation of antinociception and a variety of behavioral states like anxiety, depression, and drug abuse. KOR agonists are known to produce potent analgesic effects and have been used clinically for the treatment of pain, while KOR antagonists have shown efficacy in the treatment of anxiety and depression. This review summarizes the history, design strategy, discovery, and development of KOR ligands. KOR agonists are classified as non-biased, G protein-biased, and β-arrestin recruitment-biased, according to their degrees of bias. The mechanisms and associated effects of the G protein signaling pathway and β-arrestin recruitment signaling pathway are also discussed. Meanwhile, KOR antagonists are classified as long-acting and short-acting, based on their half-lives. In addition, we have special sections for mixed KOR agonists and selective peripheral KOR agonists. The mechanisms of action and pharmacokinetic, pharmacodynamic, and behavioral studies for each of these categories are also discussed in this review.
Keywords: Biased and unbiased agonists; G protein and β-arrestin recruitment signaling pathways; Kappa opioid receptor; Long-acting and short-acting antagonists; Mixed agonists; Selective peripheral agonists.
Copyright © 2022 Elsevier Masson SAS. All rights reserved.