Biology:Orexin receptor

From HandWiki
hypocretin (orexin) receptor 1
Identifiers
SymbolHCRTR1
NCBI gene3061
HGNC4848
OMIM602392
RefSeqNM_001525
UniProtO43613
Other data
LocusChr. 1 p33
hypocretin (orexin) receptor 2
Identifiers
SymbolHCRTR2
NCBI gene3062
HGNC4849
OMIM602393
RefSeqNM_001526
UniProtO43614
Other data
LocusChr. 6 p11-q11
Orexin receptor type 2
Identifiers
SymbolOrexin_rec2
PfamPF03827
InterProIPR004060

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 2025: oveporexton[6] and TAK-360.[7]

Ligands

Several drugs[8] 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.[9]

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),[10] two additional agents are in development: SB-649,868 by GlaxoSmithKline, for sleep disorders, and ACT-462206, currently in human clinical trials.[11] 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

  • Orexins – dual OX1 and OX2 receptor agonists
    • Orexin-A – approximately equipotent at the OX1 and OX2 receptors[2][3]
    • Orexin-B – approximately 5- to 10-fold selectivity for the OX2 receptor over the OX1 receptor[2][3]
  • AEX-5 – selective OX1 receptor agonist; also a cathepsin H inhibitor and dopamine reuptake inhibitor[12]
  • AEX-19 – dual OX1 and OX2 receptor agonist[13]
  • AEX-24 – selective OX2 receptor agonist; also an "S1R" agonist[14]

Selective

  • Alixorexton (ALKS-2680) – selective oral OX2 receptor agonist[15][16]
  • Cleminorexton – selective OX2 receptor agonist[17]
  • Danavorexton (TAK-925) – selective OX2 receptor agonist
  • E-2086 – selective OX2 receptor agonist[18]
  • Firazorexton (TAK-994) – selective OX2 receptor agonist[19][20]
  • Ledasorexton – selective OX2 receptor agonist[17]
  • Oveporexton (TAK-861) – selective OX2 receptor agonist
  • SB-668875 – selective OX2 receptor agonist
  • Suntinorexton – selective OX2 receptor agonist[19][20][21]
  • PhotOrexin – photoswitchable orexin-B analogue to control the OX2 receptor at nanomolar concentration in vivo.[22]

Antagonists

Non-selective

  • Almorexant (ACT-078573) – dual OX1 and OX2 receptor antagonist
  • Daridorexant (Quviviq; ACT-541468) – dual OX1 and OX2 receptor antagonist
  • Filorexant (MK-6096) – dual OX1 and OX2 receptor antagonist
  • GSK-649868 (SB-649868) – dual OX1 and OX2 receptor antagonist
  • Lemborexant (Dayvigo) – dual OX1 and OX2 receptor antagonist
  • Suvorexant (Belsomra) – dual OX1 and OX2 receptor antagonist
  • Vornorexant (ORN-0829, TS-142) – dual OX1 and OX2 receptor antagonist

Selective

  • ACT-335827 – selective OX1 receptor antagonist
  • AZD-4041 – selective OX1 receptor antagonist[23]
  • C4X-3256 (INDV-2000) – selective OX1 receptor antagonist[24]
  • CVN-766 – selective OX1 receptor antagonist[25]
  • EMPA – selective OX2 receptor antagonist
  • JNJ-10397049 – selective OX2 receptor antagonist
  • Nivasorexant (ACT-539313) – selective OX1 receptor antagonist
  • Rocavorexant – selective OX1 receptor antagonist
  • RTIOX-276 – selective OX1 receptor antagonist
  • SB-334867 – selective OX1 receptor antagonist
  • SB-408124 – selective OX1 receptor antagonist
  • Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – selective OX2 receptor antagonist
  • TCS-OX2-29 – selective OX2 receptor antagonist
  • Tebideutorexant (JNJ-61393215; JNJ-3215) – selective OX1 receptor antagonist

See also

References

  1. ↑ "Orexins in the regulation of the hypothalamic-pituitary-adrenal axis". Pharmacological Reviews 58 (1): 46–57. March 2006. doi:10.1124/pr.58.1.4. PMID 16507882. 
  2. ↑ 2.0 2.1 2.2 "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. 
  3. ↑ 3.0 3.1 3.2 "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. 
  4. ↑ "Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant". Nature 519 (7542): 247–250. March 2015. doi:10.1038/nature14035. PMID 25533960. 
  5. ↑ "Merck's Insomnia Medicine Belsomra C-IV Now Available in US" (in en-US). 3 February 2015. http://www.sleepreviewmag.com/2015/02/mercks-insomnia-medicine-belsomra-c-iv-now-available-us/. 
  6. ↑ Takeda (2024-09-24). A Long-term Extension Study to Evaluate the Safety and Tolerability of TAK-861 in Participants With Selected Central Hypersomnia Conditions (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT05816382. 
  7. ↑ Takeda (2025-05-15). A Randomized, Double-Blinded, Placebo-Controlled, Dose-Finding, Adaptive Trial to Evaluate the Safety, Tolerability, and Efficacy of TAK-360 in Participants With Narcolepsy Without Cataplexy (NT2) (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT06952699. 
  8. ↑ "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. doi:10.1021/bi300136h. PMID 22448975. 
  9. ↑ "The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress". Nature and Science of Sleep 8: 81–86. 2016. doi:10.2147/NSS.S76711. PMID 27051324. 
  10. ↑ "The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder". Organic Process Research & Development 15 (2): 367–375. 2011. doi:10.1021/op1002853. 
  11. ↑ "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. doi:10.1002/jcph.297. PMID 24691844. 
  12. ↑ "AEX 5". AdisInsight. Springer Nature Switzerland AG. 12 March 2024. https://adisinsight.springer.com/drugs/800077481. 
  13. ↑ "AEX 19". AdisInsight. Springer Nature Switzerland AG. 22 March 2024. https://adisinsight.springer.com/drugs/800076849. 
  14. ↑ "NLS Pharmaceutics licenses Aexon's dual orexin receptor agonists". 31 July 2024. https://www.bioworld.com/articles/706758-nls-pharmaceutics-licenses-aexons-dual-orexin-receptor-agonists?v=preview. "[...] AEX-5, an OX1R agonist, cathepsin H inhibitor and DAT reuptake inhibitor; and AEX-24, which acts as an S1R agonist and OX2R agonist. [...]" 
  15. ↑ "WHO Drug Information, Vol. 38 , No. 4, 2024". WHO. 2024. https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/pl132.pdf#page=10. 
  16. ↑ "ALKS 2680". AdisInsight. Springer Nature Switzerland AG. 7 June 2024. https://adisinsight.springer.com/drugs/800066491. 
  17. ↑ 17.0 17.1 "International Nonproprietary Names for Pharmaceutical Substances (INN)". https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/pl133.pdf. 
  18. ↑ "E-2086". AdisInsight. Springer Nature Switzerland AG. 15 July 2024. https://adisinsight.springer.com/drugs/800072674. 
  19. ↑ 19.0 19.1 "WHO Drug Information, Vol. 34, No. 2, 2020 Proposed INN: List 123 : International Nonproprietary Names for Pharmaceutical Substances (INN)". https://www.who.int/medicines/publications/druginformation/issues/INN_List-123.pdf. 
  20. ↑ 20.0 20.1 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, "Heterocyclic compound and use therof", WO patent application 2019027058, published 2019-02-07
  21. ↑ "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" 
  22. ↑ "In vivo photocontrol of orexin receptors with a nanomolar light-regulated analogue of orexin-B". Cellular and Molecular Life Sciences 81 (1). July 2024. doi:10.1007/s00018-024-05308-x. PMID 38970689. 
  23. ↑ "AZD 4041". AdisInsight. Springer Nature Switzerland AG. 31 May 2024. https://adisinsight.springer.com/drugs/800055840. 
  24. ↑ "C4X 3256". AdisInsight. Springer Nature Switzerland AG. 13 June 2024. https://adisinsight.springer.com/drugs/800056227. 
  25. ↑ "CVN 766". AdisInsight. Springer Nature Switzerland AG. 16 February 2023. https://adisinsight.springer.com/drugs/800066143. 
This article incorporates text from the public domain Pfam and InterPro: IPR004060



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Orexin_receptor&oldid=4065196"