Dalefield Martin L, Scouller Brittany, Bibi Rabia, Kivell Bronwyn M
Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
Front Pharmacol. 2022 Jun 20;13:837671. doi: 10.3389/fphar.2022.837671. eCollection 2022.
Kappa-opioid receptors (KOR) are widely expressed throughout the central nervous system, where they modulate a range of physiological processes depending on their location, including stress, mood, reward, pain, inflammation, and remyelination. However, clinical use of KOR agonists is limited by adverse effects such as dysphoria, aversion, and sedation. Within the drug-development field KOR agonists have been extensively investigated for the treatment of many centrally mediated nociceptive disorders including pruritis and pain. KOR agonists are potential alternatives to mu-opioid receptor (MOR) agonists for the treatment of pain due to their anti-nociceptive effects, lack of abuse potential, and reduced respiratory depressive effects, however, dysphoric side-effects have limited their widespread clinical use. Other diseases for which KOR agonists hold promising therapeutic potential include pruritis, multiple sclerosis, Alzheimer's disease, inflammatory diseases, gastrointestinal diseases, cancer, and ischemia. This review highlights recent drug-development efforts targeting KOR, including the development of G-protein-biased ligands, mixed opioid agonists, and peripherally restricted ligands to reduce side-effects. We also highlight the current KOR agonists that are in preclinical development or undergoing clinical trials.
κ-阿片受体（KOR）在整个中枢神经系统中广泛表达，在不同位置调节一系列生理过程，包括应激、情绪、奖赏、疼痛、炎症和髓鞘再生。然而，KOR激动剂的临床应用受到诸如烦躁不安、厌恶和镇静等不良反应的限制。在药物研发领域，KOR激动剂已被广泛研究用于治疗包括瘙痒和疼痛在内的许多中枢介导的伤害感受性疾病。由于KOR激动剂具有抗伤害感受作用、无滥用潜力且呼吸抑制作用减弱，它们是治疗疼痛的μ-阿片受体（MOR）激动剂的潜在替代品，然而，烦躁不安的副作用限制了它们在临床上的广泛应用。KOR激动剂具有潜在治疗潜力的其他疾病包括瘙痒、多发性硬化症、阿尔茨海默病、炎症性疾病、胃肠道疾病、癌症和缺血。本综述重点介绍了近期针对KOR的药物研发成果，包括G蛋白偏向性配体、混合阿片激动剂和外周限制配体的开发以减少副作用。我们还重点介绍了目前处于临床前开发或正在进行临床试验的KOR激动剂。
