Wang Xin, Gou Xiaoli, Yu Xiaojuan, Bai Dongdong, Tan Bowei, Cao Pingfeng, Qian Meilin, Zheng Xiaoxiao, Wang Hairong, Tang Pingming, Zhang Chen, Ye Fei, Ni Jia
Intensive Care Unit, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Center for Drug Research and Development, Haisco Pharmaceutical Group Co., Ltd., Chegdu, China.
Front Pharmacol. 2021 Nov 16;12:773204. doi: 10.3389/fphar.2021.773204. eCollection 2021.
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 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.
κ阿片受体（KOR）激动剂一直是很有前景的治疗候选药物，因为它们具有缓解疼痛和治疗顽固性瘙痒的潜力。尽管KOR激动剂缺乏吗啡样的中枢神经系统（CNS）效应，但确实会引起镇静、烦躁不安和利尿，这严重阻碍了它们的开发。外周限制型KOR激动剂穿透中枢神经系统的能力较差，因此与中枢神经系统相关的不良反应可以得到改善甚至消除。然而，唯一获批的外周限制型KOR激动剂CR845仍然存在一些常见的中枢神经系统不良事件。在本研究中，我们旨在研究HSK21542的药理学特性，期望为患有疼痛和瘙痒的患者提供一种安全有效的替代药物。实验结果表明，HSK21542是一种选择性强效KOR激动剂，效力高于CR845，脑/血浆浓度比为0.001，表明其具有外周选择性。在疼痛动物模型中，HSK21542显著抑制乙酸、后爪切开或慢性缩窄性损伤诱导的疼痛相关行为，给药后15分钟时的疗效与CR845相当。在扭体试验中，HSK21542具有持久的镇痛效力，给药后24小时的半数有效剂量为1.48mg/kg。同时，KOR拮抗剂nor-纳洛酮啡能有效逆转HSK21542的抗伤害感受活性。此外，HSK21542在化合物48/80诱导的瘙痒模型中具有强大的止痒活性。另一方面，HSK21542在热板试验中产生中枢抗伤害感受作用的能力较弱，对小鼠运动活动的影响较小。HSK21542不影响小鼠呼吸频率。因此，HSK21542可能是一种安全有效的KOR激动剂，是治疗疼痛和瘙痒的有前途的候选药物。
