The present and future of synthetic orexin receptor agonists

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.