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| Aliases | HCRTR1 , OX1R, Hypocretin (orexin) receptor 1, hypocretin receptor 1, ORXR1, OXR1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 602392 MGI: 2385650 HomoloGene: 37492 GeneCards: HCRTR1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Orexin receptor type 1 (Ox1R or OX1), also known as hypocretin receptor type 1 (HcrtR1), is a protein that in humans is encoded by the HCRTR1 gene. [5]
The orexin 1 receptor (OX1), is a G-protein coupled receptor that is heavily expressed in projections from the lateral hypothalamus and is involved in the regulation of feeding behaviour. OX1 selectively binds the orexin-A neuropeptide. It shares 64% identity with OX2. [5]
Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone, is caused by a lack of orexin in the brain due to destruction of the cells that produce it. It exists in the forms of Orexin-A and Orexin-B.
Wakefulness is a daily recurring brain state and state of consciousness in which an individual is conscious and engages in coherent cognitive and behavioral responses to the external world. Being awake is the opposite of the state of being asleep in which most external inputs to the brain are excluded from neural processing.
Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. Cataplexy affects approximately 70% of people who have narcolepsy, and is caused by an autoimmune destruction of hypothalamic neurons that produce the neuropeptide hypocretin, which regulates arousal and has a role in stabilization of the transition between wake and sleep states. Cataplexy without narcolepsy is rare and the cause is unknown.
The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.
The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (HCRTR1, HCRTR2).
Orexin receptor type 2 (Ox2R or OX2), also known as hypocretin receptor type 2 (HcrtR2), is a protein that in humans is encoded by the HCRTR2 gene.
Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain.
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affected also experience episodes of sudden loss of muscle strength, known as cataplexy. Narcolepsy paired with cataplexy is evidenced to be an autoimmune disorder. These experiences of cataplexy can be brought on by strong emotions. Less commonly, there may be vivid hallucinations or an inability to move while falling asleep or waking up. People with narcolepsy tend to sleep about the same number of hours per day as people without, but the quality of sleep tends to be lessened.
Almorexant, also known by its development code ACT-078573, is an orexin antagonist, acting as a competitive antagonist of the OX1 and OX2 orexin receptors, which was being developed by the pharmaceutical companies Actelion and GSK for the treatment of insomnia. Development of the drug was abandoned in January 2011 due to concerns over the hepatic safety of almorexant after transient increases in liver enzymes were observed in trials.
SB-334867 is an orexin antagonist. It was the first non-peptide antagonist developed that is selective for the orexin receptor subtype OX1, with around 50x selectivity for OX1 over OX2 receptors. It has been shown to produce sedative and anorectic effects in animals, and has been useful in characterising the orexinergic regulation of brain systems involved with appetite and sleep, as well as other physiological processes. The hydrochloride salt of SB-334867 has been demonstrated to be hydrolytically unstable, both in solution and as the solid. Orexin antagonists have multiple potential clinical applications including the treatment of drug addiction, insomnia, obesity and diabetes.
Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. Suvorexant helps with falling asleep faster, sleeping longer, being awake less in the middle of the night, and having better quality of sleep. Its effectiveness is modest, and is similar to that of other orexin antagonists, but is lower than that of benzodiazepines and Z-drugs. Suvorexant is taken by mouth.
An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one or both of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders such as insomnia.
Emmanuel Mignot is a sleep researcher and director of the Stanford Center for Sleep Sciences and Medicine, at Stanford University. Dr. Mignot is an authority on sleep research and medicine, and is mostly known for his work on narcolepsy. He is the Craig Reynolds Professor of Sleep Medicine at Stanford Medical School, Stanford University.
Thomas S. Kilduff is an American neuroscientist and the director of SRI International's Center for Neuroscience. He specializes in neurobiology related to sleep and wakefulness, and was involved in the discovery of hypocretin, a neuropeptide system that is highly involved in wakefulness regulation.
Filorexant (INN, USAN; developmental code name MK-6096) is an orexin antagonist which was under development by Merck for the treatment of insomnia, depression, diabetic neuropathy, and migraine. It is a dual antagonist of the orexin OX1 and OX2 receptors. It has a relatively short elimination half-life of 3 to 6 hours. However, it dissociates slowly from the orexin receptors and may thereby have a longer duration. Possibly in relation to this, filorexant shows next-day somnolence similarly to suvorexant. In phase 2 clinical trials, filorexant was found to be effective in the treatment of insomnia, but was not effective in the treatment of major depressive disorder, painful diabetic neuropathy, or migraine. As of May 2015, filorexant was no longer listed on Merck's online development pipeline and hence development of the drug appears to have been discontinued. Development of filorexant may have been discontinued due to lack of differentiation from suvorexant (which was also developed by Merck).
Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin antagonist medication which is under development for the treatment of depression and insomnia. It is a selective antagonist of the orexin OX2 receptor (2-SORA). The medication is taken by mouth. As of February 2022, seltorexant is in phase 3 clinical trials for treatment of major depressive disorder (MDD) and phase 2 trials for treatment of insomnia. It was also under investigation for the treatment of sleep apnea, but no recent development has been reported for this indication. Seltorexant is under development by Minerva Neurosciences and Johnson & Johnson's Janssen Pharmaceuticals.
Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.
Vornorexant, also known by its developmental code names ORN-0829 and TS-142, is an orexin antagonist medication which is under development for the treatment of insomnia and sleep apnea. It is a dual orexin OX1 and OX2 receptor antagonist (DORA). The medication is taken by mouth. As of June 2021, vornorexant is in phase 2 clinical trials for insomnia and phase 1 trials for sleep apnea. It is under development by Taisho Pharmaceutical.
TAK-994 is an orexin receptor agonist which is under development by Takeda for the treatment of narcolepsy. It is a small-molecule and orally active compound and acts as a highly selective agonist of the orexin receptor 2 (OX2) (>700-fold selectivity over the orexin receptor 1 (OX1)). TAK-994 is related to danavorexton (TAK-925). The compound reached phase 2 clinical trials for narcolepsy. However, clinical development was discontinued in October 2021 for safety reasons. The chemical structure of TAK-994 has yet to be disclosed.
ACT-539313 is an orexin antagonist medication which is under development for the treatment of binge eating disorder and was previously under development for the treatment of anxiety disorders. It is an orally active small-molecule compound with an elimination half-life of 3.3 to 6.5 hours and acts as a selective orexin OX1 receptor antagonist (1-SORA). As of May 2022, the drug is in phase 2 clinical trials for binge eating disorder. Following negative efficacy results of a phase 2 trial of ACT-539313 for binge eating disorder, Idorsia (the developer of ACT-539313) signaled in May 2022 that it would not pursue further development of the drug for this indication.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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