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Sleep disorders

Counting orexins

Nature Reviews Drug Discovery volume 6, pages 186–187 (2007)Cite this article

Orexins are produced by a discrete number of neurons in the hypothalamus, which connect to various brain regions involved in the regulation of wakefulness. Orexins and their receptors have been in the limelight since their connection with narcolepsy — a debilitating disorder in which patients spontaneously fall asleep and which is often accompanied by cataplexy — was discovered. The authors have now identified and optimized a potent, selective and competitive orexin receptor antagonist, ACT-078573, and have investigated its physiological effects after oral administration in healthy rats, dogs and humans.

Studies in rats demonstrated that the antagonist can cross the blood–brain barrier and is well tolerated even at very high doses. The effect of different doses of ACT-078573 on alertness was measured by telemetric electroencephalography and the drug was compared to the hypnotic sleep medication zolpidem, a GABA (γ-aminobutyric acid)-A receptor modulator, which is available on the market. The amount of time that animals spent in their active waking state was measured over 12 hours after administration of the drug. At doses of 30 mg kg−1 or higher, the antagonist significantly reduced the active time of the animals with a level of effect that was comparable to zolpidem. Similar observations were made in dogs, and the authors noted no drug-related loss of muscle tone and therefore no indication that the antagonist induced cataplexy. In humans, also tested at the beginning of the active part of their circadian cycle, doses of up to 1000 mg kg−1 of the antagonist were well tolerated and no severe or adverse effects were reported apart from diminished alertness and decreased latency to sleep stage 2.

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References

ORIGINAL RESEARCH PAPER

  1. Brisbare-Roch, C. et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nature Med. 13, 150–155 (2007)

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FURTHER READING

  1. Sakurai, T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nature Rev. Neurosci. 8, 171–181 (2007)

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Nature Reviews Neuroscience,

    Claudia Wiedemann

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  1. Claudia Wiedemann
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Wiedemann, C. Counting orexins. Nat Rev Drug Discov 6, 186–187 (2007). https://doi.org/10.1038/nrd2277

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  • DOI: https://doi.org/10.1038/nrd2277

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