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- Orexin receptors
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 [19]) 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 [38]. Orexin signaling has been associated with regulation of sleep and wakefulness, reward and addiction, appetite and feeding, pain gating, stress response, anxiety and depression. Currently the orexin receptor ligands in clinical use are the dual orexin receptor antagonists suvorexant and lemborexant and daridorexant, which are used as hypnotics, and several dual and OX2-selective antagonists are under development. Multiple orexin agonists are in development for the treatment of narcolepsy and other sleep disorders. Orexin receptor 3D structures have been solved [1,10-11,35,39,43-45].
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]
* Burdakov D. (2019) Reactive and predictive homeostasis: Roles of orexin/hypocretin neurons. Neuropharmacology, 154: 61-67. [PMID:30347195]
* Jacobson LH, Hoyer D, de Lecea L. (2022) Hypocretins (orexins): The ultimate translational neuropeptides. J Intern Med, 291 (5): 533-556. [PMID:35043499]
* James MH, Aston-Jones G. (2022) Orexin Reserve: A Mechanistic Framework for the Role of Orexins (Hypocretins) in Addiction. Biol Psychiatry, 92 (11): 836-844. [PMID:36328706]
Kukkonen JP. (2013) Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. Am J Physiol, Cell Physiol, 304 (1): C2-32. [PMID:23034387]
* Kukkonen JP, Jacobson LH, Hoyer D, Rinne MK, Borgland SL. (2024) International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology. Pharmacol Rev, 76 (5): 625-688. [PMID:38902035]
* Kukkonen JP, Turunen PM. (2021) Cellular Signaling Mechanisms of Hypocretin/Orexin. Front Neurol Neurosci, 45: 91-102. [PMID:34052812]
Lebold TP, Bonaventure P, Shireman BT. (2013) Selective orexin receptor antagonists. Bioorg Med Chem Lett, 23 (17): 4761-9. [PMID:23891187]
* Sakurai T, Saito YC, Yanagisawa M. (2021) Interaction between Orexin Neurons and Monoaminergic Systems. Front Neurol Neurosci, 45: 11-21. [PMID:34052806]
References
1. Asada H, Im D, Hotta Y, Yasuda S, Murata T, Suno R, Iwata S. (2022) Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor. Structure, 30 (12): 1582-1589.e4. [PMID:36417909]
2. 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]
3. 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]
4. Bonaventure P, Yun S, Johnson PL, Shekhar A, Fitz SD, Shireman BT, Lebold TP, Nepomuceno D, Lord B, Wennerholm M et al.. (2015) A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. J Pharmacol Exp Ther, 352 (3): 590-601. [PMID:25583879]
5. 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]
6. 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]
7. 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]
8. 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]
9. Evans R, Kimura H, Alexander R, Davies CH, Faessel H, Hartman DS, Ishikawa T, Ratti E, Shimizu K, Suzuki M et al.. (2022) Orexin 2 receptor-selective agonist danavorexton improves narcolepsy phenotype in a mouse model and in human patients. Proc Natl Acad Sci U S A, 119 (35): e2207531119. [PMID:35994639]
10. Hellmann J, Drabek M, Yin J, Gunera J, Pröll T, Kraus F, Langmead CJ, Hübner H, Weikert D, Kolb P et al.. (2020) Structure-based development of a subtype-selective orexin 1 receptor antagonist. Proc Natl Acad Sci U S A, 117 (30): 18059-18067. [PMID:32669442]
11. Hong C, Byrne NJ, Zamlynny B, Tummala S, Xiao L, Shipman JM, Partridge AT, Minnick C, Breslin MJ, Rudd MT et al.. (2021) Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation. Nat Commun, 12 (1): 815. [PMID:33547286]
12. Inoue A, Raimondi F, Kadji FMN, Singh G, Kishi T, Uwamizu A, Ono Y, Shinjo Y, Ishida S, Arang N et al.. (2019) Illuminating G-Protein-Coupling Selectivity of GPCRs. Cell, 177 (7): 1933-1947.e25. [PMID:31160049]
13. 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 USA, 114 (22): 5731-5736. [PMID:28507129]
14. 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]
15. Kukkonen JP. (2013) Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. Am J Physiol, Cell Physiol, 304 (1): C2-32. [PMID:23034387]
16. 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]
17. Kukkonen JP. (2016) OX2 orexin/hypocretin receptor signal transduction in recombinant Chinese hamster ovary cells. Cell Signal, 28 (2): 51-60. [PMID:26582739]
18. Kukkonen JP. (2017) Orexin/Hypocretin Signaling. Curr Top Behav Neurosci, 33: 17-50. [PMID:27909990]
19. Kukkonen JP, Jacobson LH, Hoyer D, Rinne MK, Borgland SL. (2024) International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology. Pharmacol Rev, 76 (5): 625-688. [PMID:38902035]
20. Kukkonen JP, Leonard CS. (2014) Orexin/hypocretin receptor signalling cascades. Br J Pharmacol, 171 (2): 314-31. [PMID:23902572]
21. 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]
22. Leonard CS, Kukkonen JP. (2014) Orexin/hypocretin receptor signalling: a functional perspective. Br J Pharmacol, 171 (2): 294-313. [PMID:23848055]
23. 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]
24. 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]
25. 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]
26. 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]
27. Mitsukawa K, Kimura H. (2022) Orexin 2 receptor (OX2R) protein distribution measured by autoradiography using radiolabeled OX2R-selective antagonist EMPA in rodent brain and peripheral tissues. Sci Rep, 12 (1): 8473. [PMID:35589803]
28. 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]
29. 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]
30. 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]
31. 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]
32. 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]
33. 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]
34. 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]
35. Rappas M, Ali AAE, Bennett KA, Brown JD, Bucknell SJ, Congreve M, Cooke RM, Cseke G, de Graaf C, Doré AS et al.. (2020) Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis. J Med Chem, 63 (4): 1528-1543. [PMID:31860301]
36. 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]
37. 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]
38. 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]
39. Suno R, Kimura KT, Nakane T, Yamashita K, Wang J, Fujiwara T, Yamanaka Y, Im D, Horita S, Tsujimoto H et al.. (2018) Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA. Structure, 26 (1): 7-19.e5. [PMID:29225076]
40. Treiber A, de Kanter R, Roch C, Gatfield J, Boss C, von Raumer M, Schindelholz B, Muehlan C, van Gerven J, Jenck F. (2017) The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468. J Pharmacol Exp Ther, 362 (3): 489-503. [PMID:28663311]
41. 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]
42. Yamamoto H, Nagumo Y, Ishikawa Y, Irukayama-Tomobe Y, Namekawa Y, Nemoto T, Tanaka H, Takahashi G, Tokuda A, Saitoh T et al.. (2022) OX2R-selective orexin agonism is sufficient to ameliorate cataplexy and sleep/wake fragmentation without inducing drug-seeking behavior in mouse model of narcolepsy. PLoS One, 17 (7): e0271901. [PMID:35867683]
43. 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]
44. Yin J, Kang Y, McGrath AP, Chapman K, Sjodt M, Kimura E, Okabe A, Koike T, Miyanohana Y, Shimizu Y et al.. (2022) Molecular mechanism of the wake-promoting agent TAK-925. Nat Commun, 13 (1): 2902. [PMID:35614071]
45. 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]
46. Yukitake H, Fujimoto T, Ishikawa T, Suzuki A, Shimizu Y, Rikimaru K, Ito M, Suzuki M, Kimura H. (2019) TAK-925, an orexin 2 receptor-selective agonist, shows robust wake-promoting effects in mice. Pharmacol Biochem Behav, 187: 172794. [PMID:31654653]
47. Zhang D, Perrey DA, Decker AM, Langston TL, Mavanji V, Harris DL, Kotz CM, Zhang Y. (2021) Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists. J Med Chem, 64 (12): 8806-8825. [PMID:34101446]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Jyrki P. Kukkonen
Daniel Hoyer
Gary Aston-Jones
Pascal Bonaventure
Luis de Lecea
Debbie Hartman
Laura H. Jacobson
Terrence P. McDonald
Takeshi Sakurai
Masashi Yanagisawa |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
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 [16]. Coupling of both receptors to Gi/o, Gs and and G12/13 has also been reported [12,14,20,22,34]. 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 [15]. Similarly, [Ala11, D-Leu15]orexin-B, Nag 26 and YNT-185 may show variable selectivity for OX2 receptors and may also activate OX1 receptors [33,36,42]. Thorough characterization of many antagonists and radioligands has not been published, but the situation has recently improved for many commercially available ones. Among radioligands, [3H]SB-674042, [3H]EMPA, [3H]-almorexant, [125I]orexin A (human, mouse, rat), [125I]-orexin-B and [125I][Ala11, D-Leu15]orexin-B are commercially available. [3H]-TCS 1102, [3H]Cp-1 and Rhodamine Green-orexin-A [7] are also useful labelled 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 [18,30]. Antagonists of the orexin receptors are the focus of major drug discovery efforts for their potential to treat insomnia and other disorders of wakefulness [37], while agonists would likely be useful in human narcolepsy [9,42].