2. Academic Validation
  3. Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man

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

  • Sci Rep. 2016 Jun 3;6:27147. doi: 10.1038/srep27147.
Anthony L Gotter 1,  Mark S Forman 2,  Charles M Harrell 1,  Joanne Stevens 3,  Vladimir Svetnik 4,  Ka Lai Yee 5,  Xiaodong Li 5,  Anthony J Roecker 6,  Steven V Fox 3,  Pamela L Tannenbaum 3,  Susan L Garson 1,  Inge De Lepeleire 2,  Nicole Calder 7,  Laura Rosen 7,  Arie Struyk 2,  Paul J Coleman 6,  W Joseph Herring 7,  John J Renger 1,  Christopher J Winrow 1
Affiliations

Affiliations

  • 1 Department of Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.
  • 2 Department of Translational Medicine, Merck &Co. Inc., Kenilworth, NJ, USA.
  • 3 Department of in vivo Pharmacology, Merck &Co. Inc., Kenilworth, NJ, USA.
  • 4 Department of Biostatistics and Research Decision Sciences, Merck &Co. Inc., Kenilworth, NJ, USA.
  • 5 Department of Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck &Co. Inc., Kenilworth, NJ, USA.
  • 6 Department of Medicinal Chemistry, Merck &Co. Inc., Kenilworth, NJ, USA.
  • 7 Department of Clinical Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.
PMID: 27256922 DOI: 10.1038/srep27147
Abstract

Orexin neuropeptides regulate sleep/wake through orexin receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2R-single antagonist. Preclinically, MK-1064 promotes sleep and increases both rapid eye movement (REM) and non-REM (NREM) sleep in rats at OX2R occupancies higher than the range observed for dual orexin receptor antagonists. Similar to dual antagonists, MK-1064 increases NREM and REM sleep in dogs without inducing cataplexy. Two Phase I studies in healthy human subjects evaluated safety, tolerability, pharmacokinetics and sleep-promoting effects of MK-1064, and demonstrated dose-dependent increases in subjective somnolence (via Karolinska Sleepiness Scale and Visual Analogue Scale measures) and sleep (via polysomnography), including increased REM and NREM sleep. Thus, selective OX2R antagonism is sufficient to promote REM and NREM sleep across species, similarly to that seen with dual orexin receptor antagonism.

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