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Structure-activity relationship, biological, and pharmacological characterization of the proline sulfonamide ACT-462206: a potent, brain-penetrant dual orexin 1/orexin 2 receptor antagonist.

Abstract
The orexin system consists of two G-protein-coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB-649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT-462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non-rapid eye movement (non-REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT-462206 shows anxiolytic-like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.
AuthorsChristoph Boss, Catherine Roch-Brisbare, Michel A Steiner, Alexander Treiber, Hendrik Dietrich, Francois Jenck, Markus von Raumer, Thierry Sifferlen, Christine Brotschi, Bibia Heidmann, Jodi T Williams, Hamed Aissaoui, Romain Siegrist, John Gatfield
JournalChemMedChem (ChemMedChem) Vol. 9 Issue 11 Pg. 2486-96 (Nov 2014) ISSN: 1860-7187 [Electronic] Germany
PMID25147058 (Publication Type: Journal Article)
Copyright© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Chemical References
  • ACT-462206
  • Neurotransmitter Agents
  • Orexin Receptor Antagonists
  • Orexin Receptors
  • Pyrrolidines
  • Sulfonamides
  • Proline
Topics
  • Animals
  • Blood-Brain Barrier (metabolism)
  • Brain (metabolism)
  • Dogs
  • Half-Life
  • Humans
  • Madin Darby Canine Kidney Cells
  • Male
  • Neurotransmitter Agents (chemistry, pharmacokinetics)
  • Orexin Receptor Antagonists
  • Orexin Receptors (metabolism)
  • Proline (chemistry)
  • Pyrrolidines (chemistry, pharmacokinetics)
  • Rats
  • Rats, Wistar
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides (chemistry, pharmacokinetics)

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