Hypocretin_(orexin)_receptor_2

Hypocretin (orexin) receptor 2

Hypocretin (orexin) receptor 2

Protein-coding gene in the species Homo sapiens

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.[5]

Quick Facts HCRTR2, Available structures ...
Quick Facts Orexin receptor type 2, Identifiers ...

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.[6]

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.[5] Mice with enhanced OX2 signaling are resistant to high-fat diet-induced obesity.[7]

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. [8]

Ligands

Agonists

  • Danavorexton (TAK-925) – selective OX2 receptor agonist
  • Firazorexton – selective OX2 receptor agonist[9][10]
  • Orexins – dual OX1 and OX2 receptor agonists
    • Orexin-A – approximately equipotent at the OX1 and OX2 receptors[11][12]
    • Orexin-B – approximately 5- to 10-fold selectivity for the OX2 receptor over the OX1 receptor[11][12]
  • SB-668875 – selective OX2 receptor agonist
  • Suntinorexton – selective OX2 receptor agonist[9][10]
  • TAK-861 – selective OX2 receptor agonist[13]

Antagonists

See also

References

  1. [1]
    GRCh38: Ensembl release 89: ENSG00000137252 – Ensembl, May 2017
  2. [2]
    GRCm38: Ensembl release 89: ENSMUSG00000032360 – Ensembl, May 2017
  3. [3]
    "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. [4]
    "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. [5]
    "Entrez Gene: HCRTR2 hypocretin (orexin) receptor 2".
  6. [6]
    Liszewski K (1 October 2015). "Dissecting the Structure of Membrane Proteins". Genetic Engineering & Biotechnology News. 35 (17): 16. doi:10.1089/gen.35.07.09.
  7. [7]
    Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, et al. (January 2009). "Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity". Cell Metabolism. 9 (1): 64–76. doi:10.1016/j.cmet.2008.10.010. PMC 2630400. PMID 19117547.
  8. [8]
    Warren WC, Boggs TE, Borowsky R, Carlson BM, Ferrufino E, Gross JB, et al. (March 2021). "A chromosome-level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution". Nature Communications. 12 (1): 1447. Bibcode:2021NatCo..12.1447W. doi:10.1038/s41467-021-21733-z. PMC 7933363. PMID 33664263.
  9. [9]
    "WHO Drug Information, Vol. 34, No. 2, 2020 Proposed INN: List 123 263 : International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). Who.int. Retrieved 2021-11-30.
  10. [10]
    WO application 2019027058, Kajita, Yuichi; Mikami, Satoshi & Miyanohana, Yuhei et al., "Heterocyclic compound and use therof", published 2019-02-07, assigned to Takeda Pharmaceutical Company
  11. [11]
    Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, et al. (September 1999). "Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR". British Journal of Pharmacology. 128 (1): 1–3. doi:10.1038/sj.bjp.0702780. PMC 1571615. PMID 10498827.
  12. [12]
    Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ (January 2004). "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. doi:10.1038/sj.bjp.0705610. PMC 1574197. PMID 14691055.
  13. [13]
    "Wave 1 Pipeline Market Opportunity Conference Call" (PDF). Takeda Pharmaceutical Company Limited. 8 December 2020. Archived from the original (PDF) on 2021-10-20. TAK-861, a second oral OX2R agonist will begin clinical testing in 2H FY20
  14. [14]
    McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK, et al. (August 2004). "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. doi:10.1016/j.bmcl.2004.06.032. PMID 15261275.
  15. [15]
    Roecker AJ, Mercer SP, Schreier JD, Cox CD, Fraley ME, Steen JT, et al. (February 2014). "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. doi:10.1002/cmdc.201300447. PMID 24376006. S2CID 26114114.
  16. [16]
    Kuduk SD, Skudlarek JW, DiMarco CN, Bruno JG, Pausch MH, O'Brien JA, et al. (June 2015). "Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties". Bioorganic & Medicinal Chemistry Letters. 25 (12): 2488–2492. doi:10.1016/j.bmcl.2015.04.066. PMID 25981685.
  17. [17]
    Cole AG, Stroke IL, Qin LY, Hussain Z, Simhadri S, Brescia MR, et al. (October 2008). "Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 18 (20): 5420–5423. doi:10.1016/j.bmcl.2008.09.038. PMID 18815029.
  18. [18]
    Fujimoto T, Kunitomo J, Tomata Y, Nishiyama K, Nakashima M, Hirozane M, et al. (November 2011). "Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 21 (21): 6414–6416. doi:10.1016/j.bmcl.2011.08.093. PMID 21917455.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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