Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Peptides. 2023 Sep;167:171051. doi: 10.1016/j.peptides.2023.171051. Epub 2023 Jul 6.
The neuropeptide orexin/hypocretin plays a crucial role in various physiological processes, including the regulation of sleep/wakefulness, appetite, emotion and the reward system. Dysregulation of orexin signaling has been implicated in hypersomnia, especially in narcolepsy, which is a chronic neurological disorder characterized by excessive daytime sleepiness (EDS), sudden loss of muscle tone while awake (cataplexy), sleep paralysis, and hallucinations. Small-molecule orexin receptor agonists have emerged as promising therapeutics for these disorders, and significant progress has been made in this field in the past decade. This review summarizes recent advances in the design and synthesis of orexin receptor agonists, with a focus on peptidic and small-molecule OX2R-selective, dual, and OX1R-selective agonists. The review discusses the key structural features and pharmacological properties of these agonists, as well as their potential therapeutic applications.
神经肽食欲素/下丘脑分泌素在各种生理过程中发挥着关键作用，包括睡眠/觉醒、食欲、情绪和奖励系统的调节。食欲素信号的失调与嗜睡症有关，尤其是在发作性睡病中，这是一种慢性神经障碍，其特征是白天过度嗜睡（EDS）、清醒时突然失去肌肉张力（猝倒）、睡眠瘫痪和幻觉。小分子食欲素受体激动剂已成为这些疾病的有前途的治疗方法，在过去十年中，该领域取得了重大进展。本文综述了近年来设计和合成食欲素受体激动剂的最新进展，重点介绍了肽类和小分子 OX2R 选择性、双和 OX1R 选择性激动剂。本文讨论了这些激动剂的关键结构特征和药理学特性，以及它们的潜在治疗应用。
