The hypocretin/orexin receptor: therapeutic prospective in sleep disorders.
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.
Nishino
Seiji
S
Center for Narcolepsy Research, 1201 Welch Road, MSLS Building, P 213, Palo Alto, CA 94304-5789, USA. nishino@stanford.edu
D000818:Animals; D002385:Cataplexy / Q000188:drug therapy; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009290:Narcolepsy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*
D000697:Central Nervous System Stimulants; D006993:Hypnotics and Sedatives; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide