title: Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man.
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.
authors.affiliation: Department of Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Department of Translational Medicine, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Forman
authors.affiliation: Department of Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Harrell
authors.affiliation: Department of in vivo Pharmacology, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Department of Biostatistics and Research Decision Sciences, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Svetnik
authors.affiliation: Department of Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Ka Lai
authors.initials: KL
authors.lastname: Yee
authors.affiliation: Department of Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Roecker
authors.affiliation: Department of in vivo Pharmacology, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.affiliation: Department of in vivo Pharmacology, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.affiliation: Department of Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.affiliation: Department of Translational Medicine, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Inge De
authors.initials: ID
authors.lastname: Lepeleire
authors.affiliation: Department of Clinical Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Calder
authors.affiliation: Department of Clinical Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Rosen
authors.affiliation: Department of Translational Medicine, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Arie
authors.initials: A
authors.lastname: Struyk
authors.affiliation: Department of Medicinal Chemistry, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Department of Clinical Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: Herring
authors.affiliation: Department of Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Department of Neuroscience, Merck &Co. Inc., Kenilworth, NJ, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D000068796:Orexin Receptor Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D064446:Orexin Receptors / Q000378:metabolism*; D017286:Polysomnography; D051381:Rats; D000068776:Sleep Aids, Pharmaceutical / Q000008:administration & dosage* / Q000494:pharmacology; D012894:Sleep Stages / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects
chemical_list: C578626:HCRTR2 protein, human; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068776:Sleep Aids, Pharmaceutical