title: Distinct effects of IPSU and suvorexant on mouse sleep architecture.
abstract: Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, SB-649868, suvorexant (MK-4305), and filorexant (MK-6096), have shown promise for the treatment of insomnias and sleep disorders. Whether antagonism of both OX1R and OX2R is necessary for sleep induction has been a matter of some debate. Experiments using knockout mice suggest that it may be sufficient to antagonize only OX2R. The recent identification of an orally bioavailable, brain penetrant OX2R preferring antagonist 2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (IPSU) has allowed us to test whether selective antagonism of OX2R may also be a viable strategy for induction of sleep. We previously demonstrated that IPSU and suvorexant increase sleep when dosed during the mouse active phase (lights off); IPSU inducing sleep primarily by increasing NREM sleep, suvorexant primarily by increasing REM sleep. Here, our goal was to determine whether suvorexant and IPSU affect sleep architecture independently of overall sleep induction. We therefore tested suvorexant (25 mg/kg) and IPSU (50 mg/kg) in mice during the inactive phase (lights on) when sleep is naturally more prevalent and when orexin levels are normally low. Whereas IPSU was devoid of effects on the time spent in NREM or REM, suvorexant substantially disturbed the sleep architecture by selectively increasing REM during the first 4 h after dosing. At the doses tested, suvorexant significantly decreased wake only during the first hour and IPSU did not affect wake time. These data suggest that OX2R preferring antagonists may have a reduced tendency for perturbing NREM/REM architecture in comparison with DORAs. Whether this effect will prove to be a general feature of OX2R antagonists vs. DORAs remains to be seen.
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research Basel, Switzerland ; Department of Pharmacology and Therapeutics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne Parkville, VIC, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoyer
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dürst
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research Basel, Switzerland ; Department of Pharmacology and Therapeutics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne Parkville, VIC, Australia.
authors.forename: Markus
authors.initials: M
authors.lastname: Fendt
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research Basel, Switzerland ; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne Parkville, VIC, Australia.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Betschart
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research Basel, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Hintermann
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research Basel, Switzerland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Behnke
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research Basel, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Cotesta
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research Basel, Switzerland.
authors.forename: Grit
authors.initials: G
authors.lastname: Laue
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research Basel, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Ofner
authors.affiliation: Translational Medicine, Novartis Institutes for BioMedical Research Basel, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Legangneux
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research Basel, Switzerland ; Center for Molecular Neuroscience Hamburg, Institute for Synaptic Physiology Hamburg, Germany.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Gee
keywords: REM and NREM sleep; insomnia; orexin receptor antagonist; pharmacology