Orexin receptor

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hypocretin (orexin) receptor 1
NCBI gene3061
Other data
LocusChr. 1 p33
hypocretin (orexin) receptor 2
NCBI gene3062
Other data
LocusChr. 6 p11-q11
Orexin receptor type 2

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 10-fold selectivity for orexin receptor type 2, whilst orexin-A is equipotent at both receptors.[2]

Several orexin receptor antagonists are in development for potential use in sleep disorders.[3] The first of these, Suvorexant, has been on the market in the United States since 2015.[4] There are two orexin agonists under development.[5]

Synthetic ligands[edit]

Several drugs[6] 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.[7]

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),;[8] two additional agents are in development: SB-649,868 by GlaxoSmithKline, for sleep disorders, and ACT-462206, currently in human clinical trials.[9] Another drug in development, almorexant (ACT-078573) by Actelion, was abandoned due to adverse effects.

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.

  • SB-334,867 – selective OX1 antagonist
  • SB-408,124 – selective OX1 antagonist
  • TCS-OX2-29 – selective OX2 antagonist
  • EMPA (N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) – selective OX2 antagonist
  • RTIOX-276 – selective OX1 antagonist


  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. ^ 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. ^ 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.
  4. ^ "Merck's Insomnia Medicine Belsomra C-IV Now Available in US". Sleep Review. Retrieved 2019-12-06.
  5. ^ "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.
  6. ^ 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.
  7. ^ Matthew Chow and Michelle Cao (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.CS1 maint: uses authors parameter (link)
  8. ^ 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.
  9. ^ 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.

External links[edit]

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