Beyond Benzodiazepines: The Orexin System as A Transformative Target for Sleep Pharmacotherapy

Traditional sedative-hypnotics include benzodiazepines and Z drugs.However, these drugs are accompanied by side effects such as dependence, tolerance, and next-day drowsiness.Orexin receptor antagonists represent a new class of drugs that focus on the orexin system.Orexin-A and -B, also known as hypocretin-1 and hypocretin-2, are neuropeptides produced in the lateral hypothalamus.They bind OX1 and OX2 receptors and play a crucial role in maintaining wakefulness.When orexin-producing neurons are lost, it results in narcolepsy in humans as well as in rodents.This finding has sparked interest in developing small-molecule orexin receptor antagonists as a novel therapy for insomnia.Several compounds are currently in Phase III trials.There are already marketed orexin receptor antagonists like suvorexant, lemborexant, daridorexant, vornorexant, and filorexant.While these drugs provide benefits, they also have side effects such as drowsiness, sleep paralysis, and symptoms similar to narcolepsy.Consequently, ongoing research mainly aims at creating the next generation of orexin antagonists.The primary aim is to enhance safety while reducing side effects and maintaining effectiveness for treating insomnia.