Orexin receptors: pharmacology and therapeutic opportunities

Annu Rev Pharmacol Toxicol. 2011;51:243-66. doi: 10.1146/annurev-pharmtox-010510-100528.

Abstract

Orexin-A and -B (also known as hypocretin-1 and -2) are neuropeptides produced in the lateral hypothalamus that promote many aspects of arousal through the OX1 and OX2 receptors. In fact, they are necessary for normal wakefulness, as loss of the orexin-producing neurons causes narcolepsy in humans and rodents. This has generated considerable interest in developing small-molecule orexin receptor antagonists as a novel therapy for the treatment of insomnia. Orexin antagonists, especially those that block OX2 or both OX1 and OX2 receptors, clearly promote sleep in animals, and clinical results are encouraging: Several compounds are in Phase III trials. As the orexin system mainly promotes arousal, these new compounds will likely improve insomnia without incurring many of the side effects encountered with current medications.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Drug Design
  • Humans
  • Hypnotics and Sedatives / pharmacology
  • Hypothalamus / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Neuropeptides / metabolism*
  • Orexin Receptors
  • Orexins
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / metabolism
  • Sleep Initiation and Maintenance Disorders / drug therapy*
  • Sleep Initiation and Maintenance Disorders / physiopathology

Substances

  • HCRT protein, human
  • Hypnotics and Sedatives
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexin Receptors
  • Orexins
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide