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Orexin receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [7]) 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 and some typical peptide modifications [33]. Currently the only orexin receptor ligand in clinical use is suvorexant, which is used as a hypnotic. Orexin receptor crystal structures have been solved [37-38].
Receptors
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OX1 receptor
C
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OX2 receptor
C
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Further reading
* 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]
* Burdakov D. (2019) Reactive and predictive homeostasis: Roles of orexin/hypocretin neurons. Neuropharmacology, 154: 61-67. [PMID:30347195]
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]
References
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 (1): 111-3. [PMID:12467628]
2. Bergman JM, Roecker AJ, Mercer SP, Bednar RA, Reiss DR, Ransom RW, Meacham Harrell C, Pettibone DJ, Lemaire W, Murphy KL et al.. (2008) Proline bis-amides as potent dual orexin receptor antagonists. Bioorg. Med. Chem. Lett., 18 (4): 1425-30. [PMID:18207395]
3. Callander GE, Olorunda M, Monna D, Schuepbach E, Langenegger D, Betschart C, Hintermann S, Behnke D, Cotesta S, Fendt M et al.. (2013) Kinetic properties of "dual" orexin receptor antagonists at OX1R and OX2R orexin receptors. Front Neurosci, 7: 230. [PMID:24376396]
4. 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]
5. Darker JG, Porter RA, Eggleston DS, Smart D, Brough SJ, Sabido-David C, Jerman JC. (2001) Structure-activity analysis of truncated orexin-A analogues at the orexin-1 receptor. Bioorg. Med. Chem. Lett., 11 (5): 737-40. [PMID:11266181]
6. Faedo S, Perdonà E, Antolini M, di Fabio R, Merlo Pich E, Corsi M. (2012) Functional and binding kinetic studies make a distinction between OX1 and OX2 orexin receptor antagonists. Eur. J. Pharmacol., 692 (1-3): 1-9. [PMID:22796453]
7. 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 (2): 279-88. [PMID:15914470]
8. 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]
9. Irukayama-Tomobe Y, Ogawa Y, Tominaga H, Ishikawa Y, Hosokawa N, Ambai S, Kawabe Y, Uchida S, Nakajima R, Saitoh T et al.. (2017) Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proc. Natl. Acad. Sci. U.S.A., 114 (22): 5731-5736. [PMID:28507129]
10. 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]
11. Kukkonen JP. (2013) Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. Am. J. Physiol., Cell Physiol., 304 (1): C2-32. [PMID:23034387]
12. 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]
13. Kukkonen JP. (2016) OX2 orexin/hypocretin receptor signal transduction in recombinant Chinese hamster ovary cells. Cell. Signal., 28 (2): 51-60. [PMID:26582739]
14. Kukkonen JP. (2017) Orexin/Hypocretin Signaling. Curr Top Behav Neurosci, 33: 17-50. [PMID:27909990]
15. Kukkonen JP, Leonard CS. (2014) Orexin/hypocretin receptor signalling cascades. Br. J. Pharmacol., 171 (2): 314-31. [PMID:23902572]
16. 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 (2): 340-6. [PMID:14691055]
17. Leonard CS, Kukkonen JP. (2014) Orexin/hypocretin receptor signalling: a functional perspective. Br. J. Pharmacol., 171 (2): 294-313. [PMID:23848055]
18. 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]
19. 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]
20. 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]
21. 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]
22. 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 (16): 4225-9. [PMID:15261275]
23. Mould R, Brown J, Marshall FH, Langmead CJ. (2014) Binding kinetics differentiates functional antagonism of orexin-2 receptor ligands. Br. J. Pharmacol., 171 (2): 351-63. [PMID:23692283]
24. 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]
25. 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]
26. Porter RA, Chan WN, Coulton S, Johns A, Hadley MS, Widdowson K, Jerman JC, Brough SJ, Coldwell M, Smart D et al.. (2001) 1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor. Bioorg. Med. Chem. Lett., 11 (14): 1907-10. [PMID:11459658]
27. Putula J, Kukkonen JP. (2012) Mapping of the binding sites for the OX1 orexin receptor antagonist, SB-334867, using orexin/hypocretin receptor chimaeras. Neurosci. Lett., 506 (1): 111-5. [PMID:22079339]
28. 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]
29. 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]
30. 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]
31. Rinne MK, Leino TO, Turku A, Turunen PM, Steynen Y, Xhaard H, Wallén EAA, Kukkonen JP. (2018) Pharmacological characterization of the orexin/hypocretin receptor agonist Nag 26. Eur. J. Pharmacol., 837: 137-144. [PMID:30194937]
32. 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]
33. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S et al.. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92 (4): 573-85. [PMID:9491897]
34. Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA, Jerman JC. (2001) SB-334867-A: the first selective orexin-1 receptor antagonist. Br. J. Pharmacol., 132 (6): 1179-82. [PMID:11250867]
35. Tran DT, Bonaventure P, Hack M, Mirzadegan T, Dvorak C, Letavic M, Carruthers N, Lovenberg T, Sutton SW. (2011) Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists. Eur. J. Pharmacol., 667 (1-3): 120-8. [PMID:21679703]
36. 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]
37. Yin J, Babaoglu K, Brautigam CA, Clark L, Shao Z, Scheuermann TH, Harrell CM, Gotter AL, Roecker AJ, Winrow CJ et al.. (2016) Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. Nat. Struct. Mol. Biol., 23 (4): 293-9. [PMID:26950369]
38. Yin J, Mobarec JC, Kolb P, Rosenbaum DM. (2015) Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. Nature, 519 (7542): 247-50. [PMID:25533960]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Christopher J. Winrow (Chairperson)
Paul Coleman
Luis de Lecea
Thomas Kilduff
Jyrki P. Kukkonen
Rod Porter
John Renger
Jerome M Siegel
Gregor Sutcliffe |
Other contributors:
Anthony Gotter
Jim Hagan (Past chairperson)
Rebecca Hills
Neil Upton |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: G protein-coupled receptors. Br J Pharmacol. 174 Suppl 1: S17-S129.
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The primary coupling of orexin receptors to Gq/11 proteins is rather speculative and based on the strong activation of phospholipase C, though recent studies in recombinant cells also stress the importance of Gq/11 [12]. Coupling of both receptors to Gi/o and Gs has also been reported [10,15,17,30]. For most native cellular responses observed, the G protein pathway is unknown. The relative potency order of endogenous ligands depends on the cellular signal transduction machinery [11]. Similarly, [Ala11, D-Leu15]orexin-B, Nag 26 and YNT-185 may show variable selectivity for OX2 receptors and are also likely to activate OX1 receptors [29,31]. Many antagonists and radioligands are not well-characterized, and thus the affinities are uncertain. Among radioligands, [3H]SB-674042, [3H]EMPA and [3H]-almorexant are commercially available. [3H]-TCS 1102 (pKd/OX1 8.2, pKd/OX2 9.0) [3] and Rhodamine Green-orexin-A [5] are also useful radioligand tools. Orexin receptors have been reported to be able to form complexes with each other and some other GPCRs as well as σ1 receptors, which might affect the signaling and pharmacology [14,25]. Loss-of-function mutations in the gene encoding the OX2 receptor underlie canine hereditary narcolepsy [18]. Antagonists of the orexin receptors are the focus of major drug discovery efforts for their potential to treat insomnia and other disorders of wakefulness [32], while agonists would likely be useful in human narcolepsy.