hypocretin (orexin) receptor 1 | |||||||
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Identifiers | |||||||
Symbol | HCRTR1 | ||||||
NCBI gene | 3061 | ||||||
HGNC | 4848 | ||||||
OMIM | 602392 | ||||||
RefSeq | NM_001525 | ||||||
UniProt | O43613 | ||||||
Other data | |||||||
Locus | Chr. 1 p33 | ||||||
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hypocretin (orexin) receptor 2 | |||||||
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Identifiers | |||||||
Symbol | HCRTR2 | ||||||
NCBI gene | 3062 | ||||||
HGNC | 4849 | ||||||
OMIM | 602393 | ||||||
RefSeq | NM_001526 | ||||||
UniProt | O43614 | ||||||
Other data | |||||||
Locus | Chr. 6 p11-q11 | ||||||
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Orexin receptor type 2 | |||||||||
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Identifiers | |||||||||
Symbol | Orexin_rec2 | ||||||||
Pfam | PF03827 | ||||||||
InterPro | IPR004060 | ||||||||
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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 ). [1]
Both orexin receptors exhibit a similar pharmacology – the 2 orexin peptides, orexin-A and orexin-B, bind to both receptors and, in each case, agonist binding results in an increase in intracellular calcium levels. However, orexin-B shows a 5- to 10-fold selectivity for orexin receptor type 2, whilst orexin-A is equipotent at both receptors. [2] [3]
Several orexin receptor antagonists are in development for potential use in sleep disorders. [4] The first of these, suvorexant, has been on the market in the United States since 2015. [5] There were two orexin agonists under development as of 2019 [update] . [6]
Several drugs [7] acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as narcolepsy, or orexin antagonists for insomnia. In August 2015, Nagahara et al. published their work in synthesizing the first HCRT/OX2R agonist, compound 26, with good potency and selectivity. [8]
No neuropeptide agonists are yet available, although synthetic orexin-A polypeptide has been made available as a nasal spray and tested on monkeys. One non-peptide antagonist is currently available in the U.S., Merck's suvorexant (Belsomra), [9] two additional agents are in development: SB-649,868 by GlaxoSmithKline, for sleep disorders, and ACT-462206, currently in human clinical trials. [10] Another drug in development, almorexant (ACT-078573) by Actelion, was abandoned due to adverse effects. Lemborexant, an orexin receptor antagonist, was approved for use in the United States in 2019.
Most ligands acting on the orexin system so far are polypeptides modified from the endogenous agonists orexin-A and orexin-B, however there are some subtype-selective non-peptide antagonists available for research purposes.
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.
SB-649868 is a dual orexin receptor antagonist that was being developed by GlaxoSmithKline as a treatment for insomnia.
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.
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.
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.
SB-408124 is a drug which is a non-peptide antagonist selective for the orexin receptor subtype OX1, with around 70x selectivity for OX1 over OX2 receptors, and improved oral bioavailability compared to the older OX1 antagonist SB-334867. It is used in scientific research into the function of orexinergic neurons in the body.
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 (selective orexin receptor antagonist or SORA) or both (dual orexin receptor antagonis or DORA) of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders such as insomnia.
EMPA is a selective antagonist of the OX2 receptor, with 900-fold selectivity in binding for OX2 over OX1.
Filorexant (INNTooltip International Nonproprietary Name, USANTooltip United States Approved Name; 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.
Lemborexant, sold under the brand name Dayvigo, 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. The medication is taken by mouth.
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.
Firazorexton (INNTooltip International Nonproprietary Name; development code TAK-994) is an experimental orexin 2 (OX2) receptor agonist first described in a 2019 patent filed by Takeda Pharmaceutical Company.
ACT-462206 is a dual orexin receptor antagonist (IC50 for OX1 = 60nM, OX2 = 11nM) which has been investigated for the treatment of insomnia. In human trials, ACT-462206 produced dose-dependent sedative effects and was generally well tolerated, with residual sleepiness and headache being the most common adverse events.
JNJ-61393215 is an orexin antagonist medication which is under development for the treatment of depression and anxiety disorders. It is an orally active compound and acts as a selective antagonist of the orexin OX1 receptor (1-SORA). Preliminary clinical findings suggest that JNJ-61393215 may have anti-panic effects in humans. As of November 2021, JNJ-61393215 is in phase 2 clinical trials for the treatment of major depressive disorder and is in the preclinical stage of development for treatment of panic disorder, while no further development has been reported for treatment of other anxiety disorders. The drug was originated and developed by Janssen Pharmaceuticals.
TAK-861, a second oral OX2R agonist will begin clinical testing in 2H FY20