Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [5]) are activated by the endogenous polypeptides orexin-A (HCRT, O43612) and orexin-B (HCRT, O43612) (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage [26].

The primary coupling of orexin receptors to G_q/11 proteins is rather speculative and based on the strong activation of phospholipase C, though recent studies in recombinant CHO cells also stress the importance of G_q/11 [8]. Coupling of both receptors to G_i/o and G_s has also been reported [7,11,13,24] for most cellular responses observed, the G protein pathway is unknown. The potency order of endogenous ligands may depend on the cellular signal transduction machinery. Most of the OX₂ receptor selective antagonists listed are weakly selective (≤10-fold), or selectivity may be less than 100-fold or not unequivocally determined. [Ala¹¹, D-Leu¹⁵]orexin-B may show poor OX₂ receptor selectivity [23].
Orexin receptors have been reported to be able to form complexes with each other and some other GPCRs as well as CRF receptors [10,20], which might affect the signaling and pharmacology. Recently a promising synthetic orexin receptor ligand (compound 26 [PMID: 26267383]) has been reported but not thoroughly characterized [19]. Loss-of-function mutations in the gene encoding the OX₂ receptor underlie canine hereditary narcolepsy [14]. Antagonists of the orexin receptors are the focus of major drug discovery effort for their potential to treat insomnia and other disorders of wakefulness [25], while agonists would likely be useful in human narcolepsy.

* Key recommended reading is highlighted with an asterisk

* Baimel C, Bartlett SE, Chiou LC, Lawrence AJ, Muschamp JW, Patkar O, Tung LW, Borgland SL. (2015) Orexin/hypocretin role in reward: implications for opioid and other addictions. Br. J. Pharmacol., 172 (2): 334-48. [PMID:24641197]

Boss C. (2014) Orexin receptor antagonists--a patent review (2010 to August 2014). Expert Opin Ther Pat, 24 (12): 1367-81. [PMID:25407283]

Boss C, Brisbare-Roch C, Jenck F. (2009) Biomedical application of orexin/hypocretin receptor ligands in neuroscience. J. Med. Chem., 52 (4): 891-903. [PMID:19199652]

Christopher JA. (2014) Small-molecule antagonists of the orexin receptors. Pharm Pat Anal, 3 (6): 625-38. [PMID:25489915]

Gotter AL, Webber AL, Coleman PJ, Renger JJ, Winrow CJ. (2012) International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacol. Rev., 64 (3): 389-420. [PMID:22759794]

* Kukkonen JP. (2013) Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. Am. J. Physiol., Cell Physiol., 304 (1): C2-32. [PMID:23034387]

Lebold TP, Bonaventure P, Shireman BT. (2013) Selective orexin receptor antagonists. Bioorg. Med. Chem. Lett., 23 (17): 4761-9. [PMID:23891187]

* Li SB, Jones JR, de Lecea L. (2016) Hypocretins, Neural Systems, Physiology, and Psychiatric Disorders. Curr Psychiatry Rep, 18 (1): 7. [PMID:26733323]

* Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G. (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat. Neurosci., 17 (10): 1298-303. [PMID:25254979]

Mieda M, Sakurai T. (2013) Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. Rationale for development and current status. CNS Drugs, 27 (2): 83-90. [PMID:23359095]

1. Asahi S, Egashira S, Matsuda M, Iwaasa H, Kanatani A, Ohkubo M, Ihara M, Morishima H. (2003) Development of an orexin-2 receptor selective agonist, [Ala(11), D-Leu(15)]orexin-B. Bioorg Med Chem Lett, 13: 111-113. [PMID:12467628]

2. Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van Gerven J, de Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F. (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat. Med., 13 (2): 150-5. [PMID:17259994]

3. Cox CD, Breslin MJ, Whitman DB, Schreier JD, McGaughey GB, Bogusky MJ, Roecker AJ, Mercer SP, Bednar RA, Lemaire W, Bruno JG, Reiss DR, Harrell CM, Murphy KL, Garson SL, Doran SM, Prueksaritanont T, Anderson WB, Tang C, Roller S, Cabalu TD, Cui D, Hartman GD, Young SD, Koblan KS, Winrow CJ, Renger JJ, Coleman PJ. (2010) Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J. Med. Chem., 53 (14): 5320-32. [PMID:20565075]

4. Di Fabio R, Pellacani A, Faedo S, Roth A, Piccoli L, Gerrard P, Porter RA, Johnson CN, Thewlis K, Donati D et al.. (2011) Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders. Bioorg. Med. Chem. Lett., 21 (18): 5562-7. [PMID:21831639]

5. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57: 279-288. [PMID:15914470]

6. Hirose M, Egashira S, Goto Y, Hashihayata T, Ohtake N, Iwaasa H, Hata M, Fukami T, Kanatani A, Yamada K. (2003) N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist. Bioorg. Med. Chem. Lett., 13 (24): 4497-9. [PMID:14643355]

7. Karteris E, Machado RJ, Chen J, Zervou S, Hillhouse EW, Randeva HS. (2005) Food deprivation differentially modulates orexin receptor expression and signaling in rat hypothalamus and adrenal cortex. Am. J. Physiol. Endocrinol. Metab., 288 (6): E1089-100. [PMID:15687100]

8. Kukkonen JP. (2016) G-protein-dependency of orexin/hypocretin receptor signalling in recombinant Chinese hamster ovary cells. Biochem. Biophys. Res. Commun., 476 (4): 379-85. [PMID:27237973]

9. Kukkonen JP. (2016) OX2 orexin/hypocretin receptor signal transduction in recombinant Chinese hamster ovary cells. Cell. Signal., 28 (2): 51-60. [PMID:26582739]

10. Kukkonen JP. (2017) Orexin/Hypocretin Signaling. Curr Top Behav Neurosci, 33: 17-50. [PMID:27909990]

11. Kukkonen JP, Leonard CS. (2014) Orexin/hypocretin receptor signalling cascades. Br. J. Pharmacol., 171 (2): 314-31. [PMID:23902572]

12. Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ. (2004) Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br J Pharmacol, 141: 340-346. [PMID:14691055]

13. Leonard CS, Kukkonen JP. (2014) Orexin/hypocretin receptor signalling: a functional perspective. Br. J. Pharmacol., 171 (2): 294-313. [PMID:23848055]

14. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell, 98 (3): 365-76. [PMID:10458611]

15. Malherbe P, Borroni E, Gobbi L, Knust H, Nettekoven M, Pinard E, Roche O, Rogers-Evans M, Wettstein JG, Moreau JL. (2009) Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor. Br. J. Pharmacol., 156 (8): 1326-41. [PMID:19751316]

16. Malherbe P, Borroni E, Pinard E, Wettstein JG, Knoflach F. (2009) Biochemical and electrophysiological characterization of almorexant, a dual orexin 1 receptor (OX1)/orexin 2 receptor (OX2) antagonist: comparison with selective OX1 and OX2 antagonists. Mol. Pharmacol., 76 (3): 618-31. [PMID:19542319]

17. Malherbe P, Roche O, Marcuz A, Kratzeisen C, Wettstein JG, Bissantz C. (2010) Mapping the binding pocket of dual antagonist almorexant to human orexin 1 and orexin 2 receptors: comparison with the selective OX1 antagonist SB-674042 and the selective OX2 antagonist N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). Mol. Pharmacol., 78 (1): 81-93. [PMID:20404073]

18. McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK, Dvorak CA, Lovenberg TW, Carruthers NI, Jones TK. (2004) Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists. Bioorg Med Chem Lett, 14: 4225-4229. [PMID:15261275]

19. Nagahara T, Saitoh T, Kutsumura N, Irukayama-Tomobe Y, Ogawa Y, Kuroda D, Gouda H, Kumagai H, Fujii H, Yanagisawa M et al.. (2015) Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists. J. Med. Chem., 58 (20): 7931-7. [PMID:26267383]

20. Navarro G, Quiroz C, Moreno-Delgado D, Sierakowiak A, McDowell K, Moreno E, Rea W, Cai NS, Aguinaga D, Howell LA et al.. (2015) Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine. J. Neurosci., 35 (17): 6639-53. [PMID:25926444]

21. Porter RA, Chan WN, Coulton S, Johns A, Hadley MS, Widdowson K, Jerman JC, Brough SJ, Coldwell M, Smart D, Jewitt F, Jeffrey P, Austin N. (2001) 1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor. Bioorg Med Chem Lett, 11: 1907-1910. [PMID:11459658]

22. Putula J, Pihlajamaa T, Kukkonen JP. (2014) Calcium affects OX1 orexin (hypocretin) receptor responses by modifying both orexin binding and the signal transduction machinery. Br. J. Pharmacol., 171 (24): 5816-28. [PMID:25132134]

23. Putula J, Turunen PM, Jäntti MH, Ekholm ME, Kukkonen JP. (2011) Agonist ligand discrimination by the two orexin receptors depends on the expression system. Neurosci. Lett., 494 (1): 57-60. [PMID:21362456]

24. Randeva HS, Karteris E, Grammatopoulos D, Hillhouse EW. (2001) Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis. J. Clin. Endocrinol. Metab., 86 (10): 4808-13. [PMID:11600545]

25. Roecker AJ, Cox CD, Coleman PJ. (2016) Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia. J. Med. Chem., 59 (2): 504-30. [PMID:26317591]

26. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92: 573-585. [PMID:9491897]

27. Winrow CJ, Gotter AL, Cox CD, Tannenbaum PL, Garson SL, Doran SM, Breslin MJ, Schreier JD, Fox SV, Harrell CM et al.. (2012) Pharmacological characterization of MK-6096 - A dual orexin receptor antagonist for insomnia. Neuropharmacology, 62 (2): 978-87. [PMID:22019562]

Subcommittee members: Christopher J. Winrow (Chairperson) Neuroscience Department Merck Research Laboratories West Point Pennsylvania 19486 USA Paul Coleman Medicinal Chemistry Department Merck Research Laboratories West Point Pennsylvania 19486 USA Luis de Lecea Department of Molecular Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla California 92037 USA Thomas Kilduff Molecular Neurobiology Laboratory Stanford Research Institute International Menlo Park California 94025 USA Jyrki P. Kukkonen Biochemistry and Cell Biology Department of Veterinary Biosciences University of Helsinki FIN-00014 Helsinki Finland Rod Porter Psychiatry Centre of Excellence in Drug Discovery GlaxoSmithKline New Frontiers Science Park Third Avenue Harlow Essex CM19 5AW UK John Renger Neuroscience Department Merck Research Laboratories West Point Pennsylvania 19486 USA Jerome M Siegel Department of Psychiatry and Brain Research Institute University of California Los Angeles CA 90024 USA Gregor Sutcliffe Department of Molecular Biology The Scripps Research Institute 10550 N. Torrey Pines Rd. La Jolla, California USA

Other contributors: Anthony Gotter Merck Research Laboratories West Point, PA 19486 USA Jim Hagan (Past chairperson) Psychiatry Centre of Excellence in Drug Discovery GlaxoSmithKline New Frontiers Science Park Third Avenue Harlow Essex CM19 5AW UK Rebecca Hills (Past curator) Neil Upton GlaxoSmithKline New Frontiers Science Park Third Avenue Harlow Essex CM19 5AW UK