Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia.

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.
AuthorsClaudia Betschart, Samuel Hintermann, Dirk Behnke, Simona Cotesta, Markus Fendt, Christine E Gee, Laura H Jacobson, Grit Laue, Silvio Ofner, Vinod Chaudhari, Sangamesh Badiger, Chetan Pandit, Juergen Wagner, Daniel Hoyer
JournalJournal of medicinal chemistry (J Med Chem) Vol. 56 Issue 19 Pg. 7590-607 (Oct 10 2013) ISSN: 1520-4804 [Electronic] United States
PMID23964859 (Publication Type: Journal Article)
Chemical References
  • Azepines
  • Indoles
  • Orexin Receptor Antagonists
  • Pyrimidines
  • Quinoxalines
  • Spiro Compounds
  • Triazoles
  • suvorexant
  • Animals
  • Azepines (pharmacology)
  • Electroencephalography
  • Electromyography
  • Indoles (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity (drug effects)
  • Orexin Receptor Antagonists
  • Pyrimidines (chemical synthesis, pharmacokinetics, pharmacology)
  • Quinoxalines (chemical synthesis, pharmacokinetics, pharmacology)
  • Sleep (drug effects)
  • Sleep Initiation and Maintenance Disorders (drug therapy)
  • Sleep Stages (drug effects)
  • Spiro Compounds (chemical synthesis, pharmacokinetics, pharmacology)
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triazoles (pharmacology)

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