title: Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia.
abstract: Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, 1 (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 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 antagonists 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.
authors: Global Discovery Chemistry, ‡Neuroscience, and §Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Claudia
authors: C
authors: Betschart
authors: Samuel
authors: S
authors: Hintermann
authors: Dirk
authors: D
authors: Behnke
authors: Simona
authors: S
authors: Cotesta
authors: Markus
authors: M
authors: Fendt
authors: Christine E
authors: CE
authors: Gee
authors: Laura H
authors: LH
authors: Jacobson
authors: Grit
authors: G
authors: Laue
authors: Silvio
authors: S
authors: Ofner
authors: Vinod
authors: V
authors: Chaudhari
authors: Sangamesh
authors: S
authors: Badiger
authors: Chetan
authors: C
authors: Pandit
authors: Juergen
authors: J
authors: Wagner
authors: Daniel
authors: D
authors: Hoyer
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004569:Electroencephalography; D004576:Electromyography; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D000068796:Orexin Receptor Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D012894:Sleep Stages / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology
chemical_list: D001381:Azepines; D007211:Indoles; D000068796:Orexin Receptor Antagonists; D011743:Pyrimidines; D011810:Quinoxalines; D013141:Spiro Compounds; D014230:Triazoles; C551624:suvorexant