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Polygraphic Recording Procedure for Measuring Sleep in Mice
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Published on: January 25, 2016

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Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man

Anthony L Gotter1, Mark S Forman2, Charles M Harrell1

  • 1Department of Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.

Scientific Reports
|June 4, 2016
PubMed

Insights

Selective OX2R antagonism effectively promotes sleep, including REM and NREM stages, in humans. This finding supports OX2R antagonists as a viable therapeutic strategy for sleep disorders.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Sleep Medicine

Background:

  • Orexin neuropeptides and their receptors (OX1R, OX2R) are crucial for regulating sleep-wake cycles.
  • OX2R is identified as the primary mediator for promoting arousal.
  • The efficacy of single OX2R antagonism for sleep promotion in humans remained unproven.

Purpose of the Study:

  • To evaluate the safety, tolerability, pharmacokinetics, and sleep-promoting effects of MK-1064, a selective OX2R antagonist, in healthy human subjects.
  • To determine if selective OX2R antagonism is sufficient to promote sleep, including REM and NREM sleep, across species.

Main Methods:

  • Preclinical studies in rats and dogs assessed the effects of MK-1064 on sleep architecture and cataplexy.
  • Two Phase I clinical studies in healthy human subjects were conducted.
  • Evaluated safety, tolerability, pharmacokinetics, and sleep-promoting effects using subjective measures (Karolinska Sleepiness Scale, Visual Analogue Scale) and objective polysomnography.

Main Results:

  • MK-1064 demonstrated dose-dependent increases in subjective somnolence and objective sleep duration in humans.
  • The drug increased both REM (rapid eye movement) and NREM (non-REM) sleep stages.
  • Preclinical data showed MK-1064 promoted sleep and increased REM/NREM sleep in rats and dogs without inducing cataplexy.

Conclusions:

  • Selective OX2R antagonism is sufficient to promote both REM and NREM sleep.
  • MK-1064, a single OX2R antagonist, shows potential for treating sleep disorders.
  • Findings suggest a therapeutic approach similar to dual orexin receptor antagonists but with a more targeted mechanism.

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