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Orexin (Hypocretin) Receptor Agonists and Antagonists for Treatment of Sleep Disorders

Rationale for Development and Current Status

CNS Drugs volume 27, pages 83–90 (2013)Cite this article

Abstract

Orexin A and orexin B are hypothalamic neuropeptides initially identified as endogenous ligands for two orphan G-protein coupled receptors (GPCRs). They play critical roles in the maintenance of wakefulness by regulating function of monoaminergic and cholinergic neurons that are implicated in the regulation of wakefulness. Loss of orexin neurons in humans is associated with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy, further suggesting the particular importance of orexin in the maintenance of the wakefulness state. These findings have encouraged pharmaceutical companies to develop drugs targeting orexin receptors as novel medications of sleep disorders, such as narcolepsy and insomnia. Indeed, phase III clinical trials were completed last year of suvorexant, a non-selective (dual) antagonist for orexin receptors, for the treatment of primary insomnia, and demonstrate promising results. The New Drug Application (NDA) for suvorexant has been submitted to the US FDA. Thus, the discovery of a critical role played by the orexin system in the regulation of sleep/wakefulness has opened the door of a new era for sleep medicine.

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Acknowledgements

The writing of this review was supported in part by Grants-in-Aid for Challenging Exploratory Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan. The authors declare that there are no conflicts of interest present.

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  1. Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan

    Michihiro Mieda & Takeshi Sakurai

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  1. Michihiro Mieda
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  2. Takeshi Sakurai
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Correspondence to Michihiro Mieda.

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Mieda, M., Sakurai, T. Orexin (Hypocretin) Receptor Agonists and Antagonists for Treatment of Sleep Disorders. CNS Drugs 27, 83–90 (2013). https://doi.org/10.1007/s40263-012-0036-8

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Keywords

  • Excessive Daytime Sleepiness
  • Narcolepsy
  • Sodium Oxybate
  • Primary Insomnia
  • Sleep Paralysis