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Promotion of sleep by targeting the orexin system in rats, dogs and humans


Orexins are hypothalamic peptides that play an important role in maintaining wakefulness in mammals. Permanent deficit in orexinergic function is a pathophysiological hallmark of rodent, canine and human narcolepsy. Here we report that in rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX1 and OX2 receptors. When administered orally during the active period of the circadian cycle, a dual antagonist increased, in rats, electrophysiological indices of both non-REM and, particularly, REM sleep, in contrast to GABAA receptor modulators; in dogs, it caused somnolence and increased surrogate markers of REM sleep; and in humans, it caused subjective and objective electrophysiological signs of sleep. No signs of cataplexy were observed, in contrast to the rodent, dog or human narcolepsy syndromes. These results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.

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Figure 1: The OX1/OX2 receptor antagonist decreases alertness in a dose-dependent manner in male Wistar rats.
Figure 2: The OX1/OX2 receptor antagonist decreases mobility in male Beagle dogs in a dose-dependent manner.
Figure 3: The OX1/OX2 receptor antagonist induces clinical signs of somnolence in male Beagle dogs.
Figure 4: The OX1/OX2 receptor antagonist decreases alertness in male human subjects.
Figure 5: Dose-response relationship for the effects of the OX1/OX2 receptor antagonist on latency to sleep stage S2 in male human subjects.


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Author information

Authors and Affiliations



W.F., T.W. and M.C. conceived of and initiated the project; F.J. and H.A. coordinated discovery research; R.K., H.A. and T.W. designed and synthesized ACT-078573; O.N., C.M. and W.F. cloned, expressed and screened for activity at receptors; F.J., C.B.-R., P. Hess and C.Q. designed and conducted rat and dog experiments; J.D., P. Hoover, J.v.G. and S.L.d.H. designed and conducted human experiments; M.C., M.S. and S.B. developed ACT-078573 for human testing; F.J., C.B.-R., J.D., P. Hoover and S.F. wrote the manuscript. All authors discussed and commented on the manuscript.

Corresponding author

Correspondence to François Jenck.

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Competing interests

The work described in this article was initiated and funded by Actelion Pharmaceuticals Ltd. As the majority of authors are Actelion scientists, they can be considered to have competing financial interests.

Supplementary information

Supplementary Fig. 1

Maintenance of efficacy following repeated daily oral dosing of 100 mg/kg of the OX1/OX2 receptor antagonist on pharmacodynamic measures of somnolence (NREM sleep) and home cage activity (locomotion) measured by telemetry in rats. (PDF 155 kb)

Supplementary Fig. 2

Administration of the OX1/OX2 receptor antagonist at the beginning of the quiet period. (PDF 159 kb)

Supplementary Fig. 3

Time course of the pharmacodynamic effects of the OX1/OX2 receptor antagonist in male Wistar rats. (PDF 758 kb)

Supplementary Fig. 4

Dose-response relationship for the effects of the OX1/OX2 receptor antagonist on latency to sleep stage 2 in healthy human subjects, 6.5 h after study drug administration. Comparison with 10 mg zolpidem or placebo. (PDF 108 kb)

Supplementary Table 1

Selectivity profile of the OX1/OX2 receptor antagonist ACT-078573. (PDF 339 kb)

Supplementary Table 2

Brain and systemic concentrations measured following oral administration of the OX1/OX2 receptor antagonist to male Wistar rats. (PDF 77 kb)

Supplementary Methods (PDF 111 kb)

Supplementary Note (PDF 61 kb)

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

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