The hypocretin/orexin receptor: therapeutic prospective in sleep disorders

Expert Opin Investig Drugs. 2007 Nov;16(11):1785-97. doi: 10.1517/13543784.16.11.1785.


The hypocretins (also known as orexins) and their receptors are the focus of many investigators as sites for therapeutic intervention in a number of endocrinologic, neurologic and sleep disorders. The interest for the hypocretin system is highlighted by a recent discovery that a human sleep disorder, narcolepsy, is tightly linked with the deficiency of hypocretin peptides. This finding suggests that hypocretin replacement is a promising new therapeutic intervention for human narcolepsy and related disorders, but this will only become possible when small-molecule (i.e., non-peptide) hypocretin receptor agonists become available. In contrast, high-throughput screening efforts in hypocretin receptor drug discovery programs by a number of pharmaceutical companies have already identified novel small-molecule hypocretin receptor antagonists and these antagonists may be used for the treatment of insomnia, especially for sleep-initiation problems. This is because hypocretin-deficient narcoleptic subjects show very short sleep latency and the blockade of the hypocretin receptor may induce a similar sleep symptom. At least two hypocretin receptor antagonists (ACT-078573 and GW-649868) are presently under development for the treatment of human insomnia and the promising aspects and limitations of these therapeutic interventions are discussed in this paper.

Publication types

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

MeSH terms

  • Animals
  • Cataplexy / drug therapy
  • Central Nervous System Stimulants / therapeutic use
  • Humans
  • Hypnotics and Sedatives / therapeutic use
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Narcolepsy / drug therapy*
  • Narcolepsy / metabolism
  • Narcolepsy / physiopathology
  • Neuropeptides / antagonists & inhibitors
  • 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*


  • Central Nervous System Stimulants
  • Hypnotics and Sedatives
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexin Receptors
  • Orexins
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide