hypocretin (orexin) receptor 1
Identifiers
SymbolHCRTR1
NCBI gene3061
HGNC4848
OMIM602392
RefSeqNM_001525
UniProtO43613
Other data
LocusChr. 1 p33
Search for
StructuresSwiss-model
DomainsInterPro
hypocretin (orexin) receptor 2
Identifiers
SymbolHCRTR2
NCBI gene3062
HGNC4849
OMIM602393
RefSeqNM_001526
UniProtO43614
Other data
LocusChr. 6 p11-q11
Search for
StructuresSwiss-model
DomainsInterPro
Orexin receptor type 2
Identifiers
SymbolOrexin_rec2
PfamPF03827
InterProIPR004060
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure 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.[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]

Selective

  • Danavorexton (TAK-925) – selective OX2 receptor agonist
  • Firazorexton – selective OX2 receptor agonist[11][12]
  • SB-668875 – selective OX2 receptor agonist
  • Suntinorexton – selective OX2 receptor agonist[11][12]
  • TAK-861 – selective OX2 receptor agonist[13]
  • TAK-994 – selective OX2 receptor agonist
  • ALKS-2680 -- selective oral OX² receptor agonist

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
  • EMPA – selective OX2 receptor antagonist
  • JNJ-10397049 – selective OX2 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

References

  1. ↑ Spinazzi R, Andreis PG, Rossi GP, Nussdorfer GG (2006). "Orexins in the regulation of the hypothalamic-pituitary-adrenal axis". Pharmacol. Rev. 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, Elshourbagy NA, Ellis CE, Middlemiss DN, Brown F (September 1999). "Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR". Br. J. Pharmacol. 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): 340–6. doi:10.1038/sj.bjp.0705610. PMC 1574197. PMID 14691055.
  4. ↑ Yin J, Mobarec JC, Kolb P, Rosenbaum DM (December 2014). "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, Hallett D, Manikowski DP, Pal S, Reifegerste R, Slack M, Law R (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". Nat Sci Sleep. 8: 81–6. doi:10.2147/NSS.S76711. PMC 4803263. PMID 27051324.
  9. ↑ Baxter CA, Cleator ED, Karel MJ, Edwards JS, Reamer RA, Sheen FJ, Stewart GW, Strotman NA, Wallace DJ (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 (Sep 2014). "Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant". J Clin Pharmacol. 54 (9): 979–86. doi:10.1002/jcph.297. PMID 24691844. S2CID 40714628.
  11. 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.
  12. 1 2 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
  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
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