Theorexin receptor (also referred to as thehypocretin receptor) is aG-protein-coupled receptor that binds the neuropeptideorexin. There are two variants,OX1 andOX2, each encoded by a different gene (HCRTR1,HCRTR2).[1]
Both orexin receptors exhibit a similar pharmacology – the 2 orexin peptides,orexin-A andorexin-B, bind to bothreceptors and, in each case,agonistbinding results in an increase inintracellularcalcium levels. However, orexin-B shows a 5- to 10-fold selectivity for orexin receptor type 2, whilst orexin-A isequipotent at both receptors.[2][3]
Severalorexin 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[update]:oveporexton[6] and TAK-360.[7]
Several drugs[8] acting on the orexin system are under development, either orexin agonists for the treatment of conditions such asnarcolepsy, or orexin antagonists forinsomnia. In August 2015, Nagahara et al. published their work in synthesizing the first HCRT/OX2R agonist, compound 26, with good potency and selectivity.[9]
Noneuropeptide agonists are yet available, although synthetic orexin-Apolypeptide has been made available as a nasal spray and tested on monkeys. One non-peptide antagonist is currently available in the U.S.,Merck'ssuvorexant (Belsomra),[10] two additional agents are in development:SB-649,868 byGlaxoSmithKline, for sleep disorders, and ACT-462206, currently in human clinical trials.[11] Another drug in development,almorexant (ACT-078573) byActelion, was abandoned due to adverse effects.Lemborexant, an orexin receptor antagonist, was approved for use in the United States in 2019.
Mostligands 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.
^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.PMID16507882.S2CID17941978.
^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.PMID25533960.S2CID4405254.
^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.PMID22448975.S2CID42765328.
^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.
^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.PMID24691844.S2CID40714628.
^"AEX 5".AdisInsight. Springer Nature Switzerland AG. 12 March 2024. Retrieved31 July 2024.
^"AEX 19".AdisInsight. Springer Nature Switzerland AG. 22 March 2024. Retrieved31 July 2024.
^abWO 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 toTakeda Pharmaceutical Company
