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Identification of a Novel Series of Orexin Receptor Antagonists with a Distinct Effect on Sleep Architecture for the Treatment of Insomnia

Betschart, Claudia and Hintermann, Samuel and Behnke, Dirk and Cotesta, Simona and Fendt, Markus and Gee, Christine and Jacobson, Laura and Laue, Grit and Ofner, Silvio and Chaudhari, Vinod and Badiger, Sangamesh and Pandit, Chetan and Wagner, Juergen and Hoyer, Daniel (2013) Identification of a Novel Series of Orexin Receptor Antagonists with a Distinct Effect on Sleep Architecture for the Treatment of Insomnia. Journal of Medicinal Chemistry.

Abstract

Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, SB-649868 or suvorexant, have shown promise for the treatment of insomnias and sleep disorders in several recent clinical trials in volunteers and primary insomnia patients. The relative contribution of antagonism of both OX1R and OX2R for sleep induction is still a matter of debate. We therefore initiated a drug discovery project with the aim of creating both OX2R selective and DORAs. Here we report that the OX2R selective antagonist 26 induced sleep in mice primarily by increasing NREM sleep, whereas the DORA suvorexant induced sleep largely by increasing REM sleep. Thus, OX2R selective antagonists may also be beneficial for the treatment of insomnia.

Item Type: Article
Additional Information: The key message of this paper was already released as posters and oral presentations (OAK IDs: 8114, 8195, 8427, 9667).
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/10204

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