Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.
Handb Exp Pharmacol. 2022;271:163-195. doi: 10.1007/164_2020_431.
The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system. The endogenous kappa opioid system is expressed in the central and peripheral nervous systems, and has a key role in modulating pain in central and peripheral neuronal circuits and a wide array of physiological functions and neuropsychiatric behaviors (e.g., stress, reward, emotion, motivation, cognition, epileptic seizures, itch, and diuresis). We review the latest advances in pharmacology of the KOR, chemical developments on KOR ligands with advances and challenges, and therapeutic and potential applications of KOR ligands. Diverse discovery strategies of KOR ligands targeting natural, naturally derived, and synthetic compounds with different scaffolds, as small molecules or peptides, with short or long-acting pharmacokinetics, and central or peripheral site of action, are discussed. These research efforts led to ligands with distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists. Differential modulation of KOR signaling represents a promising strategy for developing pharmacotherapies for several human diseases, either by activating (treatment of pain, pruritus, and epilepsy) or blocking (treatment of depression, anxiety, and addiction) the receptor. We focus on the recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands. Design strategies and investigations to define structure-activity relationships together with in vivo pharmacology of diphenethylamines as agonists, biased agonists, and antagonists and their potential use as therapeutics are discussed.
κ 阿片受体（KOR）是一种 G 蛋白偶联受体，其内源性配体强啡肽是阿片类神经调质系统的重要成员。内源性 κ 阿片系统在中枢和外周神经系统中表达，在调节中枢和外周神经元回路中的疼痛以及广泛的生理功能和神经精神行为（例如应激、奖赏、情绪、动机、认知、癫痫发作、瘙痒和利尿）方面发挥着关键作用。我们综述了 KOR 药理学的最新进展、KOR 配体的化学进展以及 KOR 配体的治疗和潜在应用。讨论了针对具有不同骨架的天然、天然衍生和合成化合物的 KOR 配体的各种发现策略，包括小分子或肽类、具有短或长效药代动力学以及作用于中枢或外周的配体。这些研究工作导致了具有不同药理学特性的配体，如激动剂、部分激动剂、偏向激动剂和拮抗剂。KOR 信号的差异化调节代表了开发多种人类疾病药物治疗的有前途的策略，无论是通过激活（治疗疼痛、瘙痒和癫痫）还是阻断（治疗抑郁、焦虑和成瘾）受体。我们重点介绍了二苯乙胺类新型结构独特、选择性 KOR 配体的最新化学和药理学进展。讨论了设计策略和研究以确定构效关系以及二苯乙胺类作为激动剂、偏向激动剂和拮抗剂的体内药理学及其作为治疗剂的潜在用途。
