Orexin receptor explained

hypocretin (orexin) receptor 1
Hgncid:4848
Symbol:HCRTR1
Entrezgene:3061
Omim:602392
Refseq:NM_001525
Uniprot:O43613
Chromosome:1
Arm:p
Band:33
hypocretin (orexin) receptor 2
Hgncid:4849
Symbol:HCRTR2
Entrezgene:3062
Omim:602393
Refseq:NM_001526
Uniprot:O43614
Chromosome:6
Arm:p
Band:11
Locussupplementarydata:-q11
Symbol:Orexin_rec2
Orexin receptor type 2
Pfam:PF03827
Interpro:IPR004060

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 .[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 .[6]

Ligands

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.

Agonists

Non-selective

Selective

Antagonists

See main article: Orexin antagonist.

Non-selective

Selective

External links

Notes and References

  1. Spinazzi R, Andreis PG, Rossi GP, Nussdorfer GG . Orexins in the regulation of the hypothalamic-pituitary-adrenal axis . Pharmacological Reviews . 58 . 1 . 46–57 . March 2006 . 16507882 . 10.1124/pr.58.1.4 . 17941978 .
  2. Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, Elshourbagy NA, Ellis CE, Middlemiss DN, Brown F . 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 . 10498827 . 1571615 . 10.1038/sj.bjp.0702780 .
  3. Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ . 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 . 14691055 . 1574197 . 10.1038/sj.bjp.0705610 .
  4. Yin J, Mobarec JC, Kolb P, Rosenbaum DM . Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant . Nature . 519 . 7542 . 247–250 . March 2015 . 25533960 . 10.1038/nature14035 . 4405254 .
  5. Web site: Merck's Insomnia Medicine Belsomra C-IV Now Available in US. Sleep Review. 3 February 2015. en-US. 2019-12-06.
  6. Web site: New Data Presented at World Sleep Congress Demonstrate Early Signs of Efficacy for TAK-925, a Selective Orexin Type-2 Receptor (OX2R) Agonist, in Patients with Narcolepsy Type 1. www.takeda.com. en. 2019-12-06.
  7. Heifetz A, Morris GB, Biggin PC, Barker O, Fryatt T, Bentley J, Hallett D, Manikowski D, Pal S, Reifegerste R, Slack M, Law R . Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site-directed mutagenesis . Biochemistry . 51 . 15 . 3178–3197 . April 2012 . 22448975 . 10.1021/bi300136h . 42765328 .
  8. Chow M, Cao M . The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress . Nature and Science of Sleep . 8 . 81–86 . 2016 . 27051324 . 4803263 . 10.2147/NSS.S76711 . free .
  9. Baxter CA, Cleator ED, Karel MJ, Edwards JS, Reamer RA, Sheen FJ, Stewart GW, Strotman NA, Wallace DJ . The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder . Organic Process Research & Development . 2011 . 15 . 2 . 367–375 . 10.1021/op1002853.
  10. Hoch M, van Gorsel H, van Gerven J, Dingemanse J . Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant . Journal of Clinical Pharmacology . 54 . 9 . 979–986 . September 2014 . 24691844 . 10.1002/jcph.297 . 40714628 .
  11. Web site: AEX 5 . AdisInsight . Springer Nature Switzerland AG . 12 March 2024 . 31 July 2024.
  12. Web site: AEX 19 . AdisInsight . Springer Nature Switzerland AG . 22 March 2024 . 31 July 2024.
  13. Web site: NLS Pharmaceutics licenses Aexon's dual orexin receptor agonists . BioWorld . 31 July 2024 . 31 July 2024 . [...] AEX-5, an OX1R agonist, cathepsin H inhibitor and DAT reuptake inhibitor; and AEX-24, which acts as an S1R agonist and OX2R agonist. [...].
  14. Web site: ALKS 2680 . AdisInsight . Springer Nature Switzerland AG . 7 June 2024 . 31 July 2024.
  15. Web site: E-2086 . AdisInsight . Springer Nature Switzerland AG . 15 July 2024 . 31 July 2024.
  16. Web site: WHO Drug Information, Vol. 34, No. 2, 2020 Proposed INN: List 123 : International Nonproprietary Names for Pharmaceutical Substances (INN). Who.int. 1 December 2021.
  17. WO . 2019027058 . application . Heterocyclic compound and use therof . Kajita Y, Mikami SM Miyanohana Y, Koike T, Daini M, Oyabu N, Ogino M, Takeuchi K, Ito Y, Tokunaga N, Sugimoto T, Miyazaki T, Oda T, Hoashi Y, Hattori Y, Imamura K . . 2019-02-07.
  18. Web site: Wave 1 Pipeline Market Opportunity Conference Call . TAK-861, a second oral OX2R agonist will begin clinical testing in 2H FY20 . Takeda Pharmaceutical Company Limited . 8 December 2020 . https://web.archive.org/web/20211020015502/https://fs2.magicalir.net/tdnet/2020/4502/20201208432630.pdf . 2021-10-20 .
  19. Prischich D, Sortino R, Gomila-Juaneda A, Matera C, Guardiola S, Nepomuceno D, Varese M, Bonaventure P, de Lecea L, Giralt E, Gorostiza P . In vivo photocontrol of orexin receptors with a nanomolar light-regulated analogue of orexin-B . Cellular and Molecular Life Sciences . 81 . 1 . 288 . July 2024 . 38970689 . 11335211 . 10.1007/s00018-024-05308-x .
  20. Web site: AZD 4041 . AdisInsight . Springer Nature Switzerland AG . 31 May 2024 . 31 July 2024.
  21. Web site: C4X 3256 . AdisInsight . Springer Nature Switzerland AG . 13 June 2024 . 31 July 2024.
  22. Web site: CVN 766 . AdisInsight . Springer Nature Switzerland AG . 16 February 2023 . 31 July 2024.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Orexin receptor".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2025, A B Cryer, All Rights Reserved. Cookie policy.