title: The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors.
abstract: OBJECTIVE
  Orexin peptides activate orexin 1 and orexin 2 receptors (OX(1)R and OX(2)R), regulate locomotion and sleep-wake. The dual OX(1)R/OX(2)R antagonist almorexant reduces activity and promotes sleep in multiple species, including man. The relative contributions of the two receptors in locomotion and sleep/wake regulation were investigated in mice.
  
  
  METHODS
  Mice lacking orexin receptors were used to determine the contribution of OX(1)R and OX(2)R to orexin A-induced locomotion and to almorexant-induced sleep.
  
  
  METHODS
  N/A.
  
  
  METHODS
  C57BL/6J mice and OX(1)R(+/+), OX(1)R(-/-), OX(2)R(+/+), OX(2)R(-/-) and OX(1)R(-/-)/OX(2)R(-/-) mice.
  
  
  METHODS
  Intracerebroventricular orexin A; oral dosing of almorexant.
  
  
  RESULTS
  Almorexant attenuated orexin A-induced locomotion. As in other species, almorexant dose-dependently increased rapid eye movement sleep (REM) and nonREM sleep in mice. Almorexant and orexin A were ineffective in OX(1)R(-/-)/OX(2)R(-/-) mice. Both orexin A-induced locomotion and sleep induction by almorexant were absent in OX(2)R(-/-) mice. Interestingly, almorexant did not induce cataplexy in wild-type mice under conditions where cataplexy was seen in mice lacking orexins and in OX(1)R(-/-)/OX(2)R(-/-) mice. Almorexant dissociates very slowly from OX(2)R as measured functionally and in radioligand binding. Under non equilibrium conditions in vitro, almorexant was a dual antagonist whereas at equilibrium, almorexant became OX(2)R selective.
  
  
  CONCLUSIONS
  In vivo, almorexant specifically inhibits the actions of orexin A. The two known orexin receptors mediate sleep induction by almorexant and orexin A-induced locomotion. However, OX(2)R activation mediates locomotion induction by orexin A and antagonism of OX(2)R is sufficient to promote sleep in mice.
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Géraldine M
authors.initials: GM
authors.lastname: Mang
authors.forename: Thomas
authors.initials: T
authors.lastname: Dürst
authors.forename: Hugo
authors.initials: H
authors.lastname: Bürki
authors.forename: Stefan
authors.initials: S
authors.lastname: Imobersteg
authors.forename: Dorothee
authors.initials: D
authors.lastname: Abramowski
authors.forename: Edi
authors.initials: E
authors.lastname: Schuepbach
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoyer
authors.forename: Markus
authors.initials: M
authors.lastname: Fendt
authors.forename: Christine E
authors.initials: CE
authors.lastname: Gee
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000494:pharmacology*; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000502:physiology; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000502:physiology; D012890:Sleep / Q000187:drug effects* / Q000502:physiology; D013566:Sympathomimetics / Q000494:pharmacology*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
chemical_list: D000081:Acetamides; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D013566:Sympathomimetics; C519150:almorexant