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Gene and Protein Information | ||||||
class A G protein-coupled receptor | ||||||
Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 7 | 444 | 6p12.1 | HCRTR2 | hypocretin receptor 2 | 61 |
Mouse | 7 | 460 | 9q-D | Hcrtr2 | hypocretin (orexin) receptor 2 | 14,61 |
Rat | 7 | 460 | 8q24 | Hcrtr2 | hypocretin receptor 2 | 61 |
Gene and Protein Information Comments | ||||||
Splice variants of the mouse gene are reported, generating different protein isoforms. Isoform 2 lacks amino acids 444-460 of the carboxy terminal tail compared to canonical full lenghth isoform 1. |
Previous and Unofficial Names |
hypocretin receptor 2 | orexin receptor type 2 | OX2R |
Database Links | |
Specialist databases | |
GPCRdb | ox2r_human (Hs), ox2r_mouse (Mm), ox2r_rat (Rn) |
Other databases | |
Alphafold | O43614 (Hs), P58308 (Mm), P58308-2 (Mm), P56719 (Rn) |
ChEMBL Target | CHEMBL4792 (Hs), CHEMBL2434818 (Mm), CHEMBL1275216 (Rn) |
Ensembl Gene | ENSG00000137252 (Hs), ENSMUSG00000032360 (Mm), ENSRNOG00000011251 (Rn) |
Entrez Gene | 3062 (Hs), 387285 (Mm), 25605 (Rn) |
Human Protein Atlas | ENSG00000137252 (Hs) |
KEGG Gene | hsa:3062 (Hs), mmu:387285 (Mm), rno:25605 (Rn) |
OMIM | 602393 (Hs) |
Pharos | O43614 (Hs) |
RefSeq Nucleotide | NM_001526 (Hs), NM_198962 (Mm), NM_013074 (Rn) |
RefSeq Protein | NP_001517 (Hs), NP_945200 (Mm), NP_037206 (Rn) |
SynPHARM | 6604 (in complex with suvorexant) |
UniProtKB | O43614 (Hs), P58308 (Mm), P58308-2 (Mm), P56719 (Rn) |
Wikipedia | HCRTR2 (Hs) |
Selected 3D Structures | |||||||||||||
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Natural/Endogenous Ligands |
orexin-A {Sp: Human, Mouse, Rat} |
orexin-B {Sp: Human} , orexin-B {Sp: Mouse, Rat} |
Potency order of endogenous ligands (Human) |
orexin-A (HCRT, O43612) = orexin-B (HCRT, O43612) |
Download all structure-activity data for this target as a CSV file
Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Efficacy and potency values for agonists are highly dependent on cell type, assay conditions and the readout. Agonist activity of firazorexton (TAK-994) has been demonstrated in ERK phosphorylation, CREB phosphorylation, and tuberomamillary nucleus neuron depolarization assays, with pEC50 values of 6.8, 7.4 and 7.7 respectively [32]. |
Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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View species-specific antagonist tables |
Other Binding Ligands | |||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Primary Transduction Mechanisms | |
Transducer | Effector/Response |
Gq/G11 family |
Adenylyl cyclase stimulation Adenylyl cyclase inhibition Phospholipase C stimulation Phospholipase A2 stimulation Phospholipase D stimulation |
Comments: Association with the Gq family of transducers leads to phospholipase stimulation (e.g. phospholipase families A2, C and D) and Ca2+ elevation, and with the Gi family to inhibition and with the Gs family to stimulation, respectively, of adenylyl cyclase. Ca2+/non-selective cation influx also appears to rely on Gq. However, the signal transduction has not been investigated in detail in native neurons. | |
References: 2,18,24,26,33-37,39,55,61,68 |
Tissue Distribution | ||||||||
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Tissue Distribution Comments | ||||||||
For IHC studies, it is very important to note that selectivity issues have been raised regarding antibodies for the orexin receptors which may lead to false positive/negative results and as such, mRNA expression patterns provide important confirmatory results. |
Expression Datasets | |
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Functional Assays | ||||||||||
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Physiological Functions | ||||||||
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Physiological Consequences of Altering Gene Expression | ||||||||||
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Physiological Consequences of Altering Gene Expression Comments | ||||||||||
Hcrtr2 gene disruption does not appear to result in physiological problems. |
Phenotypes, Alleles and Disease Models | Mouse data from MGI | ||||||||||||||||||
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Biologically Significant Variants | ||||||||||
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1. Akanmu MA, Honda K. (2005) Selective stimulation of orexin receptor type 2 promotes wakefulness in freely behaving rats. Brain Res, 1048 (1-2): 138-45. [PMID:15919057]
2. Ammoun S, Holmqvist T, Shariatmadari R, Oonk HB, Detheux M, Parmentier M, Akerman KE, Kukkonen JP. (2003) Distinct recognition of OX1 and OX2 receptors by orexin peptides. J Pharmacol Exp Ther, 305 (2): 507-14. [PMID:12606634]
3. 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]
4. 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]
5. Bayer L, Eggermann E, Serafin M, Saint-Mleux B, Machard D, Jones B, Mühlethaler M. (2001) Orexins (hypocretins) directly excite tuberomammillary neurons. Eur J Neurosci, 14 (9): 1571-5. [PMID:11722619]
6. 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]
7. Blanco M, López M, GarcIa-Caballero T, Gallego R, Vázquez-Boquete A, Morel G, SeñarIs R, Casanueva F, Diéguez C, Beiras A. (2001) Cellular localization of orexin receptors in human pituitary. J Clin Endocrinol Metab, 86 (7): 1616-9. [PMID:11443222]
8. Bonaventure P, Shelton J, Yun S, Nepomuceno D, Sutton S, Aluisio L, Fraser I, Lord B, Shoblock J, Welty N et al.. (2015) Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia. J Pharmacol Exp Ther, 354 (3): 471-82. [PMID:26177655]
9. 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]
10. Boss C, Roch-Brisbare C, Steiner MA, Treiber A, Dietrich H, Jenck F, von Raumer M, Sifferlen T, Brotschi C, Heidmann B et al.. (2014) Structure-activity relationship, biological, and pharmacological characterization of the proline sulfonamide ACT-462206: a potent, brain-penetrant dual orexin 1/orexin 2 receptor antagonist. ChemMedChem, 9 (11): 2486-96. [PMID:25147058]
11. Burdakov D, Liss B, Ashcroft FM. (2003) Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium--calcium exchanger. J Neurosci, 23 (12): 4951-7. [PMID:12832517]
12. Caillol M, Aioun J, Baly C, Persuy MA, Salesse R. (2003) Localization of orexins and their receptors in the rat olfactory system: possible modulation of olfactory perception by a neuropeptide synthetized centrally or locally. Brain Res, 960: 48-61. [PMID:12505657]
13. 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]
14. Chen J, Randeva HS. (2004) Genomic organization of mouse orexin receptors: characterization of two novel tissue-specific splice variants. Mol Endocrinol, 18 (11): 2790-804. [PMID:15256537]
15. Christopher JA, Aves SJ, Brown J, Errey JC, Klair SS, Langmead CJ, Mace OJ, Mould R, Patel JC, Tehan BG. (2015) Discovery of HTL6641, a dual orexin receptor antagonist with differentiated pharmacodynamic properties. Medicinal Chemistry Communications, 6: 947-955. DOI: 10.1039/C5MD00027K
16. Cluderay JE, Harrison DC, Hervieu GJ. (2002) Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul Pept, 104 (1-3): 131-44. [PMID:11830288]
17. 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]
18. Dalrymple MB, Jaeger WC, Eidne KA, Pfleger KD. (2011) Temporal profiling of orexin receptor-arrestin-ubiquitin complexes reveals differences between receptor subtypes. J Biol Chem, 286 (19): 16726-33. [PMID:21378163]
19. Eggermann E, Serafin M, Bayer L, Machard D, Saint-Mleux B, Jones BE, Mühlethaler M. (2001) Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience, 108 (2): 177-81. [PMID:11734353]
20. Eriksson KS, Sergeeva O, Brown RE, Haas HL. (2001) Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci, 21 (23): 9273-9. [PMID:11717361]
21. Fitch TE, Benvenga MJ, Jesudason CD, Zink C, Vandergriff AB, Menezes MM, Schober DA, Rorick-Kehn LM. (2014) LSN2424100: a novel, potent orexin-2 receptor antagonist with selectivity over orexin-1 receptors and activity in an animal model predictive of antidepressant-like efficacy. Front Neurosci, 8: 5. [PMID:24478625]
22. 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]
23. 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]
24. Hoang QV, Bajic D, Yanagisawa M, Nakajima S, Nakajima Y. (2003) Effects of orexin (hypocretin) on GIRK channels. J Neurophysiol, 90 (2): 693-702. [PMID:12702704]
25. Holmqvist T, Akerman KE, Kukkonen JP. (2001) High specificity of human orexin receptors for orexins over neuropeptide Y and other neuropeptides. Neurosci Lett, 305 (3): 177-80. [PMID:11403934]
26. Holmqvist T, Akerman KE, Kukkonen JP. (2002) Orexin signaling in recombinant neuron-like cells. FEBS Lett, 526 (1-3): 11-4. [PMID:12208495]
27. Holmqvist T, Johansson L, Ostman M, Ammoun S, Akerman KE, Kukkonen JP. (2005) OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms. J Biol Chem, 280 (8): 6570-9. [PMID:15611118]
28. 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]
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40. López M, Señarís R, Gallego R, García-Caballero T, Lago F, Seoane L, Casanueva F, Diéguez C. (1999) Orexin receptors are expressed in the adrenal medulla of the rat. Endocrinology, 140 (12): 5991-4. [PMID:10579367]
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42. 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]
43. 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]
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