Biology:Hypocretin (orexin) receptor 2
From HandWiki
Short description: Protein-coding gene in the species Homo sapiens
 Generic protein structure example |
| Orexin receptor type 2 | |||||||||
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| Identifiers | |||||||||
| Symbol | Orexin_rec2 | ||||||||
| Pfam | PF03827 | ||||||||
| InterPro | IPR004060 | ||||||||
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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.[1]
Structure
The structure of the receptor has been solved to 2.5 Å resolution as a fusion protein bound to suvorexant using lipid-mediated crystallization.[2]
Function
OX2 is a G-protein coupled receptor expressed exclusively in the brain. It has 64% identity with OX1. OX2 binds both orexin A and orexin B neuropeptides. OX2 is involved in the central feedback mechanism that regulates feeding behaviour.[1] Mice with enhanced OX2 signaling are resistant to high-fat diet-induced obesity.[3]
This receptor is activated by Hipocretin, which is a wake-promoting hypothalamic neuropeptide that acts as a critical regulator of sleep in animals as Zebrafish or Mammals. This protein has mutations in Astyanax mexicanus that reduces the sleep needs of the cavefish. [4]
Ligands
Agonists
- Danavorexton (TAK-925) – selective OX2 receptor agonist
- Firazorexton – selective OX2 receptor agonist[5][6]
- Orexins – dual OX1 and OX2 receptor agonists
- SB-668875 – selective OX2 receptor agonist
- Suntinorexton – selective OX2 receptor agonist[5][6]
- TAK-861 – selective OX2 receptor agonist[9]
- TAK-994 – selective OX2 receptor agonist
Antagonists
- Almorexant - Dual OX1 and OX2 antagonist
- Daridorexant (nemorexant) - Dual OX1 and OX2 antagonist
- EMPA - Selective OX2 antagonist
- Filorexant - Dual OX1 and OX2 antagonist
- JNJ-10397049 (600x selective for OX2 over OX1)[10]
- Lemborexant - Dual OX1 and OX2 antagonist
- MK-1064 - Selective OX2 antagonist[11]
- MK-8133 - Selective OX2 antagonist[12]
- SB-649,868 - Dual OX1 and OX2 antagonist
- Seltorexant - Selective OX2 antagonist
- Suvorexant - Dual OX1 and OX2 antagonist
- TCS-OX2-29 - Selective OX2 antagonist
- (3,4-dimethoxyphenoxy)alkylamino acetamides[13]
- Compound 1m - Selective OX2 antagonist[14]
See also
References
- ↑ 1.0 1.1 "Entrez Gene: HCRTR2 hypocretin (orexin) receptor 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3062.
- ↑ Liszewski, Kathy (1 October 2015). "Dissecting the Structure of Membrane Proteins". Genetic Engineering & Biotechnology News 35 (17): 16. doi:10.1089/gen.35.07.09. http://www.genengnews.com/gen-articles/dissecting-the-structure-of-membrane-proteins/5583/.
- ↑ "Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity". Cell Metabolism 9 (1): 64–76. January 2009. doi:10.1016/j.cmet.2008.10.010. PMID 19117547.
- ↑ "A chromosome-level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution". Nature Communications 12 (1): 1447. March 2021. doi:10.1038/s41467-021-21733-z. PMID 33664263.
- ↑ 5.0 5.1 "WHO Drug Information, Vol. 34, No. 2, 2020 Proposed INN: List 123 263 : International Nonproprietary Names for Pharmaceutical Substances (INN)". https://www.who.int/medicines/publications/druginformation/issues/INN_List-123.pdf.
- ↑ 6.0 6.1 Kajita, Yuichi; Satoshi Mikami & Yuhei Miyanohana et al., "Heterocyclic compound and use therof", WO patent application 2019027058, published 2019-02-07
- ↑ 7.0 7.1 "Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR". British Journal of Pharmacology 128 (1): 1–3. September 1999. doi:10.1038/sj.bjp.0702780. PMID 10498827.
- ↑ 8.0 8.1 "Characterisation of the binding of [3H-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor"]. British Journal of Pharmacology 141 (2): 340–346. January 2004. doi:10.1038/sj.bjp.0705610. PMID 14691055.
- ↑ "Wave 1 Pipeline Market Opportunity Conference Call". Takeda Pharmaceutical Company Limited. 8 December 2020. https://fs2.magicalir.net/tdnet/2020/4502/20201208432630.pdf. "TAK-861, a second oral OX2R agonist will begin clinical testing in 2H FY20"
- ↑ "Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists". Bioorganic & Medicinal Chemistry Letters 14 (16): 4225–4229. August 2004. doi:10.1016/j.bmcl.2004.06.032. PMID 15261275.
- ↑ "Discovery of 5-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3-terpyridine-3'-carboxamide (MK-1064): a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia". ChemMedChem 9 (2): 311–322. February 2014. doi:10.1002/cmdc.201300447. PMID 24376006.
- ↑ "Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties". Bioorganic & Medicinal Chemistry Letters 25 (12): 2488–2492. June 2015. doi:10.1016/j.bmcl.2015.04.066. PMID 25981685.
- ↑ "Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters 18 (20): 5420–5423. October 2008. doi:10.1016/j.bmcl.2008.09.038. PMID 18815029.
- ↑ "Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters 21 (21): 6414–6416. November 2011. doi:10.1016/j.bmcl.2011.08.093. PMID 21917455.
Further reading
- "Obesity and the hypothalamus: novel peptides for new pathways". Cell 92 (4): 437–440. February 1998. doi:10.1016/S0092-8674(00)80937-X. PMID 9491885.
- "To eat or to sleep? Orexin in the regulation of feeding and wakefulness". Annual Review of Neuroscience 24: 429–458. 2001. doi:10.1146/annurev.neuro.24.1.429. PMID 11283317.
- "Hypocretin/orexin, sleep and narcolepsy". BioEssays 23 (5): 397–408. May 2001. doi:10.1002/bies.1058. PMID 11340621.
- "The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity". Proceedings of the National Academy of Sciences of the United States of America 95 (1): 322–327. January 1998. doi:10.1073/pnas.95.1.322. PMID 9419374. Bibcode: 1998PNAS...95..322D.
- "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior". Cell 92 (4): 573–585. February 1998. doi:10.1016/S0092-8674(00)80949-6. PMID 9491897.
- "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior". Cell 92 (5): 1 page following 696. March 1998. doi:10.1016/S0092-8674(02)09256-5. PMID 9527442.
- "A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains". Nature Medicine 6 (9): 991–997. September 2000. doi:10.1038/79690. PMID 10973318.
- "Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function". Immunity 13 (2): 233–242. August 2000. doi:10.1016/S1074-7613(00)00023-6. PMID 10981966.
- "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–1795. November 2000. doi:10.1101/gr.143000. PMID 11076863.
- "Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade". The Journal of Clinical Endocrinology and Metabolism 86 (2): 778–782. February 2001. doi:10.1210/jcem.86.2.7233. PMID 11158046.
- "Cellular localization of orexin receptors in human pituitary". The Journal of Clinical Endocrinology and Metabolism 86 (4): 1616–1619. April 2001. doi:10.1210/jcem.86.7.7433. PMID 11297593.
- "Cellular localization of orexin receptors in human pituitary". The Journal of Clinical Endocrinology and Metabolism 86 (7): 1616–1619. July 2001. doi:10.1210/jcem.86.7.7433. PMID 11443222.
- "Expression and coupling characteristics of the CRH and orexin type 2 receptors in human fetal adrenals". The Journal of Clinical Endocrinology and Metabolism 86 (9): 4512–4519. September 2001. doi:10.1210/jcem.86.9.7849. PMID 11549701.
- "Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis". The Journal of Clinical Endocrinology and Metabolism 86 (10): 4808–4813. October 2001. doi:10.1210/jcem.86.10.7921. PMID 11600545.
- "Polymorphisms in hypocretin/orexin pathway genes and narcolepsy". Neurology 57 (10): 1896–1899. November 2001. doi:10.1212/wnl.57.10.1896. PMID 11723285.
- "Cellular localization of orexin receptors in human adrenal gland, adrenocortical adenomas and pheochromocytomas". Regulatory Peptides 104 (1–3): 161–165. March 2002. doi:10.1016/S0167-0115(01)00359-7. PMID 11830291.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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