School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand (K.P., D.V.A., B.M.K.) and Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky (S.K., T.P.).
School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand (K.P., D.V.A., B.M.K.) and Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky (S.K., T.P.)
J Pharmacol Exp Ther. 2020 Nov;375(2):332-348. doi: 10.1124/jpet.120.000134. Epub 2020 Sep 10.
There is significant need to find effective, nonaddictive pain medications. 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 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 , , or nociceptin opioid receptor activation to obtain mixed opioid receptor agonists, therefore negating the adverse effects and retaining the therapeutic effect.
寻找有效且无成瘾性的止痛药物具有重要意义。阿片受体（KOPr）激动剂已被研究了数十年，但最近由于其镇痛作用和潜在滥用风险低而受到越来越多的关注。然而，一系列副作用限制了这些药物的临床开发。目前有几种策略可用于开发更安全、更有效的 KOPr 激动剂。这些策略包括确定 G 蛋白偏向性激动剂、开发无中枢介导副作用的外周受限 KOPr 激动剂，以及开发混合阿片受体激动剂，以特定比例针对多个受体，平衡副作用谱并减少耐受性。本文综述了与治疗疼痛相关的 KOPr 激动剂研究的最新进展。意义：本综述讨论了开发更安全的阿片受体（KOPr）激动剂的策略，这些激动剂具有治疗疼痛的潜力。虽然一种策略是修饰选择性 KOPr 激动剂以产生外周受限或 G 蛋白偏向性结构，但另一种方法是将 KOPr 激动剂与 μ、δ 或孤啡肽受体激活相结合，以获得混合阿片受体激动剂，从而消除不良反应并保留治疗效果。
