Abstract
Kappa opioid receptor (KOR) agonists have been promising therapeutic candidates, owing to their potential for relieving pain and treating intractable pruritus. Although lacking morphine-like central nervous system (CNS) effects, KOR agonists do elicit sedation, dysphoria and diuresis which seriously impede their development. Peripherally-restricted KOR agonists have a poor ability to penetrate into the CNS system, so that CNS-related adverse effects can be ameliorated or even abolished. However, the only approved peripherally-restricted KOR agonist CR845 remains some frequent CNS adverse events. In the present study, we aim to address pharmacological profiles of HSK21542, with an expectation to provide a safe and effective alternative for patients who are suffering from pain and pruritus. The in vitro experimental results showed that HSK21542 was a selective and potent KOR agonist with higher potency than CR845, and had a brain/plasma concentration ratio of 0.001, indicating its peripheral selectivity. In animal models of pain, HSK21542 significantly inhibited acetic acid-, hindpaw incision- or chronic constriction injury-induced pain-related behaviors, and the efficacy was comparable to CR845 at 15 min post-dosing. HSK21542 had a long-lasting analgesic potency with a median effective dose of 1.48 mg/kg at 24 h post-drug in writhing test. Meanwhile, the antinociceptive activity of HSK21542 was effectively reversed by a KOR antagonist nor-binaltorphimine. In addition, HSK21542 had powerful antipruritic activities in compound 48/80-induced itch model. On the other hand, HSK21542 had a weak ability to produce central antinociceptive effects in a hot-plate test and fewer effects on the locomotor activity of mice. HSK21542 didn’t affect the respiratory rate of mice. Therefore, HSK21542 might be a safe and effective KOR agonist and promising candidate for treating pain and pruritus.
Highlights
Kappa opioid receptor (KOR), one of the classical opioid receptors, is an inhibitory G-protein coupled receptor (GPCR) that is distributed in both the central nervous system (CNS) and the peripheral tissues (Ragen et al, 2015; Snyder et al, 2018)
U69593, a positive control, obviously prevented [3H]diprenorphine binding to KOR with an 50% inhibitory concentration (IC50) value of 14.72 nM
HSK21542 significantly inhibited [3H]diprenorphine binding to KOR with an IC50 value of 0.54 nM, while CR845 had an IC50 value of 1.16 nM
Summary
Kappa opioid receptor (KOR), one of the classical opioid receptors, is an inhibitory G-protein coupled receptor (GPCR) that is distributed in both the central nervous system (CNS) and the peripheral tissues (Ragen et al, 2015; Snyder et al, 2018). The development of centrally penetrating KOR agonists is severely limited due to its unpleasant adverse events, and only one centrally penetrating KOR agonist nalfurafine has been approved so far for the treatment of pruritus in Japan (Inui, 2015). To avoid these adverse side effects, other approaches have been attempted for developing the KOR agonists, and the biased KOR agonists and peripherally-restricted KOR agonists among these have gained much attention. The development of biased KOR agonists was based on the concept that G-protein coupled receptors (GPCRs) can selectively signal in different contexts (Violin et al, 2014). The concept of biased opioid receptor agonist has met with less enthusiasm
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