Orexin receptor

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. Only the crystal structure of OX2 is known.^[3]

Selective ligands

Several drugs^[4] acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as narcolepsy, or orexin antagonists for insomnia. No non-peptide agonists are yet available, although synthetic Orexin-A polypeptide has been made available as a nasal spray and tested on monkeys. Several non-peptide antagonists are in development however; SB-649,868 by GlaxoSmithKline for sleep disorders is a non-selective orexin receptor antagonist. Another dual orexin antagonist, almorexant (ACT-078573) by Actelion, was abandoned because of side effects. A third entry is Merck's suvorexant (Belsomra),^[5] which has recently been approved for use. A new antagonist compound, ACT-462206, was recently studied in humans.^[6]

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

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. 
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. doi:10.1038/nature14035. 
4. ↑ 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. 
5. ↑ 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. 
6. ↑ "Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant". J Clin Pharmacol. 54: 979–86. Sep 2014. doi:10.1002/jcph.297. PMID 24691844. 

External links

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

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