Orexin Receptor Antagonists

This paper focuses on the role of orexin receptors in sleep as evidenced in recent preclinical and clinical work. Orexin A and B and their two receptors (OX1R and OX2R) play essential roles in arousal and sleep/wake regulation, addiction, and stress. The absence of orexin producing cells in the lateral hypothalamus or of orexins in the CSF results in narcolepsy with cataplexy in humans. This finding and others on sleep phenotypes in orexin or orexin receptor knockout mice have triggered drug discovery programs on orexin receptor (OXR) antagonists for the treatment of insomnia and other disorders. Several OXR antagonists, most of which are dual OX1R/OX2R antagonists (dual orexin receptor antagonists (DORAs)), have now reached phase II/III clinical trials. Suvorexant (Belsomra®), recently registered in Japan, USA, and Australia for insomnia, is the first orexinergic hypnotic principle of this new class. DORAs promote sleep primarily by increasing REM sleep, with little effect on slow wave sleep (SWS). Based on rodent studies, it is clear that the OX2R is the primary target mediating sleep promotion by DORAs. We briefly review preclinical and clinical data of OXR antagonists in situations of unperturbed and perturbed sleep, e.g., insomnia and various neurological diseases. We propose that REM sleep enhancement by DORAs may provide opportunities to treat specific neurological disorders. By contrast, OX2R antagonists such as seltorexant (JNJ-54717793/MIN-202) or MK-1064 may have broader applications as they appear to promote balanced sleep architecture in preclinical models and should, in theory, have a lower narcoleptic/cataplectic potential. These concepts require further validation as more OXR antagonists move beyond early stages of clinical development.