Hypocretin (orexin) receptor 2

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]

HCRTR2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHCRTR2, OX2R, Hypocretin (orexin) receptor 2, hypocretin receptor 2, ORXR2, OXR2
External IDsOMIM: 602393 MGI: 2680765 HomoloGene: 1168 GeneCards: HCRTR2
Orthologs
SpeciesHumanMouse
Entrez

3062

387285

Ensembl

ENSG00000137252

ENSMUSG00000032360

UniProt

O43614

P58308

RefSeq (mRNA)

NM_001526
NM_001384272

NM_198962
NM_001364551

RefSeq (protein)

NP_001517

NP_945200
NP_001351480

Location (UCSC)Chr 6: 55.11 – 55.28 MbChr 9: 76.13 – 76.23 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Orexin receptor type 2
Identifiers
SymbolOrexin_rec2
PfamPF03827
InterProIPR004060
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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]
  • TAK-994 – selective OX2 receptor agonist

Antagonists

See also

References

  1. GRCh38: Ensembl release 89: ENSG00000137252 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000032360 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: HCRTR2 hypocretin (orexin) receptor 2".
  6. 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.
  7. Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, Yanagisawa M (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. 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. doi:10.1038/s41467-021-21733-z. PMC 7933363. PMID 33664263.
  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. 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. 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. 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. "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. 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. 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. 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. 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. 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.

This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.