Orexin OX2 Receptor Antagonists as Sleep Aids

  • Laura H. Jacobson
  • Sui Chen
  • Sanjida Mir
  • Daniel Hoyer
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 33)


The discovery of the orexin system represents the single major progress in the sleep field of the last three to four decades. The two orexin peptides and their two receptors play a major role in arousal and sleep/wake cycles. Defects in the orexin system lead to narcolepsy with cataplexy in humans and dogs and can be experimentally reproduced in rodents. At least six orexin receptor antagonists have reached Phase II or Phase III clinical trials in insomnia, five of which are dual orexin receptor antagonists (DORAs) that target both OX1 and OX2 receptors (OX2Rs). All clinically tested DORAs induce and maintain sleep: suvorexant, recently registered in the USA and Japan for insomnia, represents the first hypnotic principle that acts in a completely different manner from the current standard medications. It is clear, however, that in the clinic, all DORAs promote sleep primarily by increasing rapid eye movement (REM) and are almost devoid of effects on slow-wave (SWS) sleep. At present, there is no consensus on whether the sole promotion of REM sleep has a negative impact in patients suffering from insomnia. However, sleep onset REM (SOREM), which has been documented with DORAs, is clearly an undesirable effect, especially for narcoleptic patients and also in fragile populations (e.g. elderly patients) where REM-associated loss of muscle tone may promote an elevated risk of falls. Debate thus remains as to the ideal orexin agent to achieve a balanced increase in REM and non-rapid eye movement (NREM) sleep. Here, we review the evidence that an OX2R antagonist should be at least equivalent, or perhaps superior, to a DORA for the treatment of insomnia. An OX2R antagonist may produce more balanced sleep than a DORA. Rodent sleep experiments show that the OX2R is the primary target of orexin receptor antagonists in sleep modulation. Furthermore, an OX2R antagonist should, in theory, have a lower narcoleptic/cataplexic potential. In the clinic, the situation remains equivocal, since OX2R antagonists are in early stages: MK-1064 has completed Phase I, and MIN202 is currently in clinical Phase II/III trials. However, data from insomnia patients have not yet been released. Promotional material suggests that balanced sleep is indeed induced by MIN-202, whereas in volunteers MK-1064 has been reported to act similarly to DORAs.


Insomnia NREM sleep Orexin receptor antagonist OX2REM sleep 



Selective orexin 2 receptor antagonist


Bed nucleus of the stria terminalis


Committee for Medicinal Products for Human Use


Central nervous system


Cerebrospinal fluid


Dorsomedial hypothalamic nuclei


Dual orexin receptor antagonist




Dorsal raphe


Designer receptors exclusively activated by designer drugs


Direct transitions between wake and REM sleep


Diagnostic and Statistical Manual of Mental Disorders Fourth/Fifth edition

DTA mice

Mice in which selective orexin neuron loss is engineered by inducible expression of diphtheria toxin A


Excessive daytime sleepiness


European Medicines Agency


US Food and Drug Administration


Gamma-aminobutyric acid A receptor








Locus coeruleus


Laterodorsal tegmental nucleus


Lateral hypothalamus


Lateral pontine tegmentum


Median preoptic nucleus


Non-rapid eye movement sleep




Orexin receptor


Orexin 1 receptor


Orexin 2 receptor


Parabrachial nucleus




Pedunculopontine tegmental area




Rapid eye movement sleep


Suprachiasmatic nucleus


Selective orexin receptor antagonist


Sleep onset REM


Sublaterodorsal nucleus


Slow-wave sleep


Tuberomammillary nucleus


Total sleep time


Ventrolateral periaqueductal grey


Ventrolateral preoptic area


Ventral periaqueductal grey


Ventral tegmental area


Wake after sleep onset


Wild type

Z drugs

Non-benzodiazepine site GABAA receptor positive allosteric modulators; the current market-leading hypnotics (zopiclone, zolpidem, eszopiclone, zaleplon)


Zeitgeber time (ZT0 and ZT24 = lights on, ZT12 = lights off)


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© Springer International Publishing AG 2016

Open Access This chapter is distributed under the terms of the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Authors and Affiliations

  • Laura H. Jacobson
    • 1
    • 2
  • Sui Chen
    • 2
  • Sanjida Mir
    • 2
  • Daniel Hoyer
    • 1
    • 2
    • 3
  1. 1.The Florey Institute of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  2. 2.Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health SciencesThe University of MelbourneParkvilleAustralia
  3. 3.Department of Chemical PhysiologyThe Scripps Research InstituteLa JollaUSA

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