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Distinct effects of orexin 2 receptor antagonism and dual orexin 1,2 receptor antagonism on sleep architecture in mice.

Hoyer, Daniel and Duerst, Thomas and Fendt, Markus and Jacobson, Laura and Betschart, Claudia and Hintermann, Samuel and Behnke, Dirk and Cotesta, Simona and Laue, Grit and Ofner, Silvio and Legangneux, Eric and Gee, Christine (2013) Distinct effects of orexin 2 receptor antagonism and dual orexin 1,2 receptor antagonism on sleep architecture in mice. Frontiers in Neuroscience, Neuropharmacology..

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 selective 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 directly test whether selective antagonism of OX2R may also be a viable strategy for induction of sleep. We have previously demonstrated that IPSU and suvorexant increase sleep when dosed during the mouse active phase (lights off); IPSU achieving this primarily by increasing NREM sleep, suvorexant primarily by increasing REM sleep. Here, we tested the effects of suvorexant and IPSU during the inactive phase (lights on), in order to determine their effects on sleep architecture during a phase when sleep is naturally more prevalent. At the doses tested, only suvorexant further decreased wake during the inactive period and only during the first hour after drug application. 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 hours after dosing. Thus, OX2R selective 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 SORAs versus DORAs remains to be seen.

Item Type: Article
Additional Information: All compounds used in this study are either competitor compounds (from the public domain) or have been previously released
Keywords: orexin receptor antagonist, insomnia, pharmacology, REM and NREM sleep
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/10933

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