Orexin receptor

Last updated

hypocretin (orexin) receptor 1
Identifiers
SymbolHCRTR1
NCBI gene 3061
HGNC 4848
OMIM 602392
RefSeq NM_001525
UniProt O43613
Other data
Locus Chr. 1 p33
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Structures Swiss-model
Domains InterPro
hypocretin (orexin) receptor 2
Identifiers
SymbolHCRTR2
NCBI gene 3062
HGNC 4849
OMIM 602393
RefSeq NM_001526
UniProt O43614
Other data
Locus Chr. 6 p11-q11
Search for
Structures Swiss-model
Domains InterPro
Orexin receptor type 2
Identifiers
SymbolOrexin_rec2
Pfam PF03827
InterPro IPR004060
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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]

Contents

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

Selective

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

References

  1. ↑ Spinazzi R, Andreis PG, Rossi GP, Nussdorfer GG (March 2006). "Orexins in the regulation of the hypothalamic-pituitary-adrenal axis". Pharmacological Reviews. 58 (1): 46–57. doi:10.1124/pr.58.1.4. PMID   16507882. S2CID   17941978.
  2. 1 2 3 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.
  3. 1 2 3 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.
  4. ↑ Yin J, Mobarec JC, Kolb P, Rosenbaum DM (March 2015). "Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant". Nature. 519 (7542): 247–250. doi:10.1038/nature14035. PMID   25533960. S2CID   4405254.
  5. ↑ "Merck's Insomnia Medicine Belsomra C-IV Now Available in US". Sleep Review. 3 February 2015. Retrieved 2019-12-06.
  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.
  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.
  8. ↑ Heifetz A, Morris GB, Biggin PC, Barker O, Fryatt T, Bentley J, et al. (April 2012). "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. doi:10.1021/bi300136h. PMID   22448975. S2CID   42765328.
  9. ↑ Chow M, Cao M (2016). "The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress". Nature and Science of Sleep. 8: 81–86. doi: 10.2147/NSS.S76711 . PMC   4803263 . PMID   27051324.
  10. ↑ Baxter CA, Cleator ED, Karel MJ, Edwards JS, Reamer RA, Sheen FJ, et al. (2011). "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. doi:10.1021/op1002853.
  11. ↑ Hoch M, van Gorsel H, van Gerven J, Dingemanse J (September 2014). "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. doi:10.1002/jcph.297. PMID   24691844. S2CID   40714628.
  12. ↑ "AEX 5". AdisInsight. Springer Nature Switzerland AG. 12 March 2024. Retrieved 31 July 2024.
  13. ↑ "AEX 19". AdisInsight. Springer Nature Switzerland AG. 22 March 2024. Retrieved 31 July 2024.
  14. ↑ "NLS Pharmaceutics licenses Aexon's dual orexin receptor agonists". BioWorld. 31 July 2024. Retrieved 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. [...]
  15. ↑ "WHO Drug Information, Vol. 38 , No. 4, 2024" (PDF). WHO. 2024. Retrieved 29 May 2025.
  16. ↑ "ALKS 2680". AdisInsight. Springer Nature Switzerland AG. 7 June 2024. Retrieved 31 July 2024.
  17. 1 2 "International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). Archived from the original (PDF) on 2025-07-17.
  18. ↑ "E-2086". AdisInsight. Springer Nature Switzerland AG. 15 July 2024. Retrieved 31 July 2024.
  19. 1 2 "WHO Drug Information, Vol. 34, No. 2, 2020 Proposed INN: List 123 : International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). Who.int. Retrieved 1 December 2021.
  20. 1 2 WOapplication 2019027058,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",published 2019-02-07, assigned to Takeda Pharmaceutical Company
  21. ↑ "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
  22. ↑ Prischich D, Sortino R, Gomila-Juaneda A, Matera C, Guardiola S, Nepomuceno D, et al. (July 2024). "In vivo photocontrol of orexin receptors with a nanomolar light-regulated analogue of orexin-B". Cellular and Molecular Life Sciences. 81 (1) 288. doi:10.1007/s00018-024-05308-x. PMC   11335211 . PMID   38970689.
  23. ↑ "AZD 4041". AdisInsight. Springer Nature Switzerland AG. 31 May 2024. Retrieved 31 July 2024.
  24. ↑ "C4X 3256". AdisInsight. Springer Nature Switzerland AG. 13 June 2024. Retrieved 31 July 2024.
  25. ↑ "CVN 766". AdisInsight. Springer Nature Switzerland AG. 16 February 2023. Retrieved 31 July 2024.
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