Orexin receptor

hypocretin (orexin) receptor 1
Identifiers
Symbol	HCRTR1
NCBI gene	3061
HGNC	4848
OMIM	602392
RefSeq	NM_001525
UniProt	O43613
Other data
Locus	Chr. 1 p33
Search for Structures Swiss-model Domains InterPro

hypocretin (orexin) receptor 2
Identifiers
Symbol	HCRTR2
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
Symbol	Orexin_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]

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 2019^[update].[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

• 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[11]
• AEX-19 – dual OX₁ and OX₂ receptor agonist[12]
• AEX-24 – selective OX2 receptor agonist; also an "S1R" agonist[13]

Selective

• ALKS-2680 — selective oral OX₂ receptor agonist[14]
• Danavorexton (TAK-925) – selective OX₂ receptor agonist
• E-2086 – selective OX₂ receptor agonist[15]
• Firazorexton (TAK-994) – selective OX₂ receptor agonist[16][17]
• Oveporexton – selective OX₂ receptor agonist
• SB-668875 – selective OX₂ receptor agonist
• Suntinorexton (TAK-861) – selective OX₂ receptor agonist[16][17][18]
• PhotOrexin – photoswitchable orexin-B analogue to control the OX₂ receptor at nanomolar concentration in vivo.[19]

Antagonists

Main article: Orexin antagonist

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[20]
• C4X-3256 (INDV-2000) – selective OX₁ receptor antagonist[21]
• CVN-766 – selective OX₁ receptor antagonist[22]
• EMPA – selective OX₂ receptor antagonist
• JNJ-10397049 – selective OX₂ receptor antagonist
• Nivasorexant (ACT-539313) – 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. 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. 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. "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. Retrieved 2019-12-06.
7. 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.
8. 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.
9. 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.
10. 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.
11. "AEX 5". AdisInsight. Springer Nature Switzerland AG. 12 March 2024. Retrieved 31 July 2024.
12. "AEX 19". AdisInsight. Springer Nature Switzerland AG. 22 March 2024. Retrieved 31 July 2024.
13. "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. [...]
14. "ALKS 2680". AdisInsight. Springer Nature Switzerland AG. 7 June 2024. Retrieved 31 July 2024.
15. "E-2086". AdisInsight. Springer Nature Switzerland AG. 15 July 2024. Retrieved 31 July 2024.
16. "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.
17. WO application 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 
18. "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
19. 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.
20. "AZD 4041". AdisInsight. Springer Nature Switzerland AG. 31 May 2024. Retrieved 31 July 2024.
21. "C4X 3256". AdisInsight. Springer Nature Switzerland AG. 13 June 2024. Retrieved 31 July 2024.
22. "CVN 766". AdisInsight. Springer Nature Switzerland AG. 16 February 2023. Retrieved 31 July 2024.

External links

• "Orexin Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Orexin+Receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the public domain Pfam and InterPro: IPR004060