OX<sub>2</sub> receptor | Orexin receptors | IUPHAR/BPS Guide to PHARMACOLOGY

Top ▲

OX2 receptor

Target not currently curated in GtoImmuPdb

Target id: 322

Nomenclature: OX2 receptor

Family: Orexin receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

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 50
Mouse 7 460 9q-D Hcrtr2 hypocretin (orexin) receptor 2 13,50
Rat 7 460 8q24 Hcrtr2 hypocretin receptor 2 50
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 | hypocretin (orexin) receptor 2
Database Links
Specialist databases
GPCRDB ox2r_human (Hs), ox2r_mouse (Mm), ox2r_rat (Rn)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human OX2 orexin receptor bound to the antagonist suvorexant.
Ligand:  suvorexant
Resolution:  2.5Å
Species:  Human
References:  62
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

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[Ala11, D-Leu15]orexin-B Hs Full agonist 7.6 – 9.9 pEC50 3,44
pEC50 7.6 – 9.9 [3,44]
orexin-A {Sp: Human, Mouse, Rat} Hs Full agonist 6.5 – 10.0 pEC50 2,21,23,28-29,41,50,52,55,64
pEC50 6.5 – 10.0 [2,21,23,28-29,41,50,52,55,64]
orexin-B {Sp: Human} Hs Full agonist 6.5 – 10.0 pEC50 2,21,23,41,50,52,55,64
pEC50 6.5 – 10.0 [2,21,23,41,50,52,55,64]
Nag 26 Hs Agonist 7.6 pEC50 39,47
pEC50 7.6 (EC50 2.3x10-8 M) [39,47]
YNT-185 Hs Agonist 7.6 pEC50 25,39
pEC50 7.6 (EC50 2.8x10-8 M) [25,39]
[125I]-orexin-A Hs Agonist - - 29,43,50
Useful working concentration sub nM-low nM. [29,43,50]
Agonist Comments
Efficacy/potenct values for agonists are highly dependent on the assay conditions and the readout.
Note that compound 26 is a recently identified small molecule agonist, subject to additional characterization.
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]-almorexant Hs Antagonist 8.9 – 9.8 pKd 34-35
pKd 8.9 – 9.8 (Kd 1.25x10-9 – 1.58x10-10 M) [34-35]
[3H]Cp-1 Hs Antagonist 9.2 – 9.4 pKd 34
pKd 9.2 – 9.4 (Kd 6.3x10-10 – 4x10-10 M) [34]
[3H]EMPA Hs Antagonist 8.6 – 9.0 pKd 33,35
pKd 8.6 – 9.0 (Kd 2.51x10-9 – 1x10-9 M) [33,35]
[3H]SB-674042 Hs Antagonist 6.9 pKd 30,34
pKd 6.9 [30,34]
TCS 1102 Hs Antagonist 9.7 pKi 5
pKi 9.7 (Ki 2x10-10 M) [5]
SB-649868 Hs Antagonist 8.9 – 9.8 pKi 12,15
pKi 8.9 – 9.8 [12,15]
MK-1064 Hs Antagonist 9.3 pKi 48
pKi 9.3 (Ki 5x10-10 M) [48]
suvorexant Hs Antagonist 8.9 – 9.5 pKi 12,15,38
pKi 8.9 – 9.5 [12,15,38]
filorexant Hs Antagonist 8.9 – 9.1 pKi 12,15,60
pKi 8.9 – 9.1 [12,15,60]
MK-3697 Hs Antagonist 9.0 pKi 49
pKi 9.0 (Ki 1.1x10-9 M) [49]
Cp-1 Hs Antagonist 8.5 – 9.3 pKi 33-34
pKi 8.5 – 9.3 [33-34]
EMPA Hs Antagonist 8.4 – 9.2 pKi 33-35,38,56
pKi 8.4 – 9.2 300–3000-fold selective [33-35,38,56]
lemborexant Hs Antagonist 8.5 pKi 63
pKi 8.5 (Ki 3x10-9 M) [63]
Description: In vitro radioligand binding assay
LSN2424100 Hs Antagonist 8.4 pKi 19
pKi 8.4 (Ki 4.5x10-9 M) [19]
compound 11 [PMID: 15261275] Hs Antagonist 8.3 pKi 36
pKi 8.3 (Ki 5.01x10-9 M) [36]
Description: Radioligand displacement assay using [125I]-orexin A as radio ligand.
seltorexant Rn Antagonist 8.1 pKi 7
pKi 8.1 (Ki 7.9x10-9 M) [7]
Description: In vitro radioligand binding assay
JNJ-10397049 Hs Antagonist 7.7 – 8.4 pKi 15,36,56
pKi 7.7 – 8.4 200–800-fold selective [15,36,56]
seltorexant Hs Antagonist 8.0 pKi 7
pKi 8.0 (Ki 1x10-8 M) [7]
Description: In vitro radioligand binding assay
TCS-OX2-29 Hs Antagonist 6.9 – 7.5 pKi 5,20
pKi 6.9 – 7.5 [5,20]
compound 1 [PMID: 15261275] Hs Antagonist 6.8 – 7.1 pKi 36
pKi 6.8 – 7.1 [36]
SB-674042 Hs Antagonist 6.9 pKi 31
pKi 6.9 (Ki 1.29x10-7 M) [31]
SB-408124 Hs Antagonist 5.7 – 6.0 pKi 30,34
pKi 5.7 – 6.0 [30,34]
SB-334867 Hs Antagonist 5.2 – 6.3 pKi 34,42
pKi 5.2 – 6.3 [34,42]
almorexant Hs Antagonist 8.1 pIC50 9
pIC50 8.1 (IC50 7.94x10-9 M) [9]
ACT-462206 Hs Antagonist 8.0 pIC50 8
pIC50 8.0 (IC50 1.1x10-8 M) [8]
ACT-335827 Hs Antagonist 6.3 – 6.6 pIC50 53
pIC50 6.3 – 6.6 (IC50 4.71x10-7 – 2.71x10-7 M) [53]
ACT-335827 Rn Antagonist 6.0 – 6.2 pIC50 53
pIC50 6.0 – 6.2 (IC50 1.03x10-6 – 6.3x10-7 M) [53]
View species-specific antagonist tables
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family
Gi/Go family
Gq/G11 family
Adenylate cyclase stimulation
Adenylate cyclase inhibition
Phospholipase C stimulation
Comments:  Association with the Gq family of transducers leads to phospholipase C stimulation, 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:  2,16,21,23,27,46,50,55
Tissue Distribution
Pituitary: corticotroph cells.
Species:  Human
Technique:  Immunohistochemistry
References:  6
OX: brain, lung, spleen, testis.
OX: skeletal muscle, testis, spleen > brain, lung > liver, kidney.
Species:  Mouse
Technique:  PCR
References:  13
Lymph node > bone marrow, spleen > thymus > lung > liver > kidney > spinal cord.
Species:  Mouse
Technique:  RT-PCR
References:  24
CNS: highest levels found in the cerebral neocortex, basal ganglia, hippocampal formation, hypothalamus, thalamus, midbrain, reticular formation.
Species:  Rat
Technique:  Immunohistochemistry
References:  14
Adrenal medulla.
Species:  Rat
Technique:  RT-PCR and immunohistrochemistry
References:  32
Olfactory system: olfactory mucosa (olfactory epithelium and lamina propria) > olfactory bulb, anterior olfactory nuclei and piriform cortex, hypothalamic and amygdala nuclei.
Species:  Rat
Technique:  immunocytochemistry
References:  11
CNS: highest levels found in the brainstem, hypothalamus, thalamus > dorsal root ganglia.
Species:  Rat
Technique:  RT-PCR
References:  14
CNS: highest levels found in the cerebral cortex, nucleus accumbens, subthalamic and paraventricular thalamic nuclei, anterior pretectal nucleus.
Species:  Rat
Technique:  in situ hybridisation
References:  57
Tuberomammillary (TM) neurons in the hypothalamus.
Species:  Rat
Technique:  RT-PCR
References:  18
Pancreatic islets.
Species:  Rat
Technique:  RT-PCR
References:  40
Brainstem: lateral reticular field (LRt) and the nucleus of the solitary tract (NTS).
Species:  Rat
Technique:  in situ hybridisation
References:  54
Pineal gland.
Species:  Rat
Technique:  RT-PCR
References:  37
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

Show »

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

There should be a chart of expression data here, you may need to enable JavaScript!
Functional Assays
Adenylyl cyclase and phospholipase C activation and Ca2+ elevation in HEK293 cells transfected with OX2.
Species:  Human
Tissue:  HEK293 cells
Response measured:  cAMP and inositol phosphate accumulation, Ca2+ elevation
References:  44,55
Measurement of membrane conductance in HEK 293 cells transfected with the OX2 receptor and GIRK channels.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Biphasic response: Initial phase of GIRK activation (both PTX-sensitive and insensitive) followed by long-lasting GIRK inhibition (PTX-insensitive only).
References:  21
Measurement of Ca2+ and cAMP levels in BIM hybridoma cells transfected with the OX2 receptor.
Species:  Rat
Tissue:  BIM cells
Response measured:  PTX-sensitive inhibition of cAMP accumulation and PTX-insensitive increase in [Ca2+].
References:  64
Ca2+ elevation and phospholipase C activation in CHO-K1 cells transfected with the OX2 receptor.
Species:  Human
Tissue:  CHO-K1 cells.
Response measured:  PLC activity, (PLC-mediated) release of Ca2+ from intracellular stores followed by Ca2+ influx.. Possibly also receptor-operated Ca2+ influx
References:  2,22,28-29,50,52
Measurement of membrane conductance in a mixed population of tuberomammillary (TM) neurons endogenously expressing the OX2 receptor.
Species:  Rat
Tissue:  TM neurons.
Response measured:  Supression of GIRK current.
References:  21
Orexin-induced programmed cell death in CHO-S cells transfected with the OX2 receptor.
Species:  Human
Tissue:  CHO-S cells
Response measured:  Cell death
References:  58
Activation of phospholipase C and D, diacylglycerol lipase and arachidonic acid release, and regulation of adenylyl cyclase in CHO-K1 cells transfected with the OX2 receptor.
Species:  Human
Tissue:  CHO-K1 cells
Response measured:  PLC, PLD and diacylglycerol lipase activity, arachidonic acid release, adenylyl cyclase activity.
References:  28-29
Activation of ERK and p38 MAPK pathways in HEK293 cells transfected with the OX2 receptor.
Species:  Human
Tissue:  HEK293 cells
Response measured:  Stimulation of ERK and p38 phosphorylation (Western blotting)
References:  55
Physiological Functions
Stimulation of food intake.
Species:  Rat
Tissue:  In vivo.
References:  50
Excitation of neurons known to contribute to wakefulness.
Species:  Rat
Tissue:  Tuberomammillary (TM) nuclei from histaminergic neurons..
References:  4,18
Excitation of GABAergic neurons.
Species:  Rat
Tissue:  Septohippocampal GABAergic neurons.
References:  61
Neuronal excitation of GABAergic neurones via the Na-Ca exchanger.
Species:  Mouse
Tissue:  Arcuate nucleus (ARC) neurons.
References:  10
Excitation of neurons known to be involved in the control of motivated behaviors.
Species:  Rat
Tissue:  Paraventricular nuclei of the thalamus (PVT).
References:  26
Increase in wake duration and decrease in REM and non-REM sleep.
Species:  Rat
Tissue:  In vivo.
References:  1
Inhibition of β-adrenoceptor-induced melatonin secretion and N-acetlytransferase (NAT) activity.
Species:  Rat
Tissue:  Dissociated pinealocytes.
References:  37
Excitation of neurons known to contribute to wakefulness.
Species:  Rat
Tissue:  Basal forebrain (BF) cholinergic neurons.
References:  17
Ethanol induced self-administration, place preference and behavioral reinstatement blocked by selective OX2 receptor antagonist, JNJ-10397049
Species:  Rat
Tissue:  Systemic (subcutaneous administration)
References:  51
Physiological Consequences of Altering Gene Expression
OX2 receptor knockout mice exhibit disrupted wakefulness, abnormal attacks of non-REM sleep and elimination of orexin-evoked excitation of histaminergic neurons in the hypothalamus.
Species:  Mouse
Technique:  Gene targeting in embryonic stem cells.
References:  59
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

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Hcrtr2tm1Ywa Hcrtr2tm1Ywa/Hcrtr2tm1Ywa
involves: 129S6/SvEvTac * C57BL/6J
MGI:2680765  MP:0001501 abnormal sleep pattern PMID: 12797957 
Hcrtr2tm1Ywa Hcrtr2tm1Ywa/Hcrtr2tm1Ywa
involves: 129S6/SvEvTac * C57BL/6J
MGI:2680765  MP:0005279 narcolepsy PMID: 12797957 
Biologically Significant Variants
Type:  Splice variant
Species:  Mouse
Description:  C-terminal splice variant of the mouse OX2 receptor, OX
Amino acids:  443
References:  13
Type:  Splice variant
Species:  Mouse
Description:  C-terminal splice variant of the OX2 receptor, OX. This variant is not found in skeletal muscle or the kidney and is upregulated in response to food deprivation.
Amino acids:  460
References:  13
Type:  Single nucleotide polymorphism
Species:  Human
Description:  This single nucleotide polymorphism is associated with a 5 fold higher risk of developing cluster headaches (CHs).
Nucleotide change:  1246G>A
References:  45


Show »

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. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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]

23. Holmqvist T, Akerman KE, Kukkonen JP. (2002) Orexin signaling in recombinant neuron-like cells. FEBS Lett., 526 (1-3): 11-4. [PMID:12208495]

24. 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]

25. 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]

26. Ishibashi M, Takano S, Yanagida H, Takatsuna M, Nakajima K, Oomura Y, Wayner MJ, Sasaki K. (2005) Effects of orexins/hypocretins on neuronal activity in the paraventricular nucleus of the thalamus in rats in vitro. Peptides, 26 (3): 471-81. [PMID:15652654]

27. Karteris E, Randeva HS, Grammatopoulos DK, Jaffe RB, Hillhouse EW. (2001) Expression and coupling characteristics of the CRH and orexin type 2 receptors in human fetal adrenals. J. Clin. Endocrinol. Metab., 86 (9): 4512-9. [PMID:11549701]

28. 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]

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

30. 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]

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

32. 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]

33. 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]

34. 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]

35. 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]

36. 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]

37. Mikkelsen JD, Hauser F, deLecea L, Sutcliffe JG, Kilduff TS, Calgari C, Pévet P, Simonneaux V. (2001) Hypocretin (orexin) in the rat pineal gland: a central transmitter with effects on noradrenaline-induced release of melatonin. Eur. J. Neurosci., 14 (3): 419-25. [PMID:11553292]

38. 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]

39. 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]

40. Nowak KW, Strowski MZ, Switonska MM, Kaczmarek P, Singh V, Fabis M, Mackowiak P, Nowak M, Malendowicz LK. (2005) Evidence that orexins A and B stimulate insulin secretion from rat pancreatic islets via both receptor subtypes. Int. J. Mol. Med., 15 (6): 969-72. [PMID:15870901]

41. Okumura T, Takeuchi S, Motomura W, Yamada H, Egashira Si S, Asahi S, Kanatani A, Ihara M, Kohgo Y. (2001) Requirement of intact disulfide bonds in orexin-A-induced stimulation of gastric acid secretion that is mediated by OX1 receptor activation. Biochem. Biophys. Res. Commun., 280 (4): 976-81. [PMID:11162621]

42. 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]

43. 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]

44. 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]

45. Rainero I, Gallone S, Valfrè W, Ferrero M, Angilella G, Rivoiro C, Rubino E, De Martino P, Savi L, Ferrone M et al.. (2004) A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology, 63 (7): 1286-8. [PMID:15477554]

46. 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]

47. 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]

48. Roecker AJ, Mercer SP, Schreier JD, Cox CD, Fraley ME, Steen JT, Lemaire W, Bruno JG, Harrell CM, Garson SL et al.. (2014) Discovery of 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064): a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia. ChemMedChem, 9 (2): 311-22. [PMID:24376006]

49. Roecker AJ, Reger TS, Mattern MC, Mercer SP, Bergman JM, Schreier JD, Cube RV, Cox CD, Li D, Lemaire W et al.. (2014) Discovery of MK-3697: a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia. Bioorg. Med. Chem. Lett., 24 (20): 4884-90. [PMID:25248679]

50. 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]

51. Shoblock JR, Welty N, Aluisio L, Fraser I, Motley ST, Morton K, Palmer J, Bonaventure P, Carruthers NI, Lovenberg TW et al.. (2011) Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement. Psychopharmacology (Berl.), 215 (1): 191-203. [PMID:21181123]

52. Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, Elshourbagy NA, Ellis CE, Middlemiss DN, Brown F. (1999) Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR. Br. J. Pharmacol., 128 (1): 1-3. [PMID:10498827]

53. Steiner MA, Gatfield J, Brisbare-Roch C, Dietrich H, Treiber A, Jenck F, Boss C. (2013) Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist. ChemMedChem, 8 (6): 898-903. [PMID:23589487]

54. Sunter D, Morgan I, Edwards CM, Dakin CL, Murphy KG, Gardiner J, Taheri S, Rayes E, Bloom SR. (2001) Orexins: effects on behavior and localisation of orexin receptor 2 messenger ribonucleic acid in the rat brainstem. Brain Res., 907 (1-2): 27-34. [PMID:11430882]

55. Tang J, Chen J, Ramanjaneya M, Punn A, Conner AC, Randeva HS. (2008) The signalling profile of recombinant human orexin-2 receptor. Cell. Signal., 20 (9): 1651-61. [PMID:18599270]

56. 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]

57. Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett, 438: 71-75. [PMID:9821961]

58. Voisin T, Firar AE, Avondo V, Laburthe M. (2006) Orexin-induced apoptosis: the key role of the seven-transmembrane domain orexin type 2 receptor. Endocrinology, 147 (10): 4977-84. [PMID:16857748]

59. Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, Marcus JN, Lee C, Elmquist JK, Kohlmeier KA et al.. (2003) Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron, 38 (5): 715-30. [PMID:12797957]

60. 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]

61. Wu M, Zhang Z, Leranth C, Xu C, van den Pol AN, Alreja M. (2002) Hypocretin increases impulse flow in the septohippocampal GABAergic pathway: implications for arousal via a mechanism of hippocampal disinhibition. J. Neurosci., 22 (17): 7754-65. [PMID:12196599]

62. 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]

63. Yoshida Y, Naoe Y, Terauchi T, Ozaki F, Doko T, Takemura A, Tanaka T, Sorimachi K, Beuckmann CT, Suzuki M et al.. (2015) Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist. J. Med. Chem., 58 (11): 4648-64. [PMID:25953512]

64. Zhu Y, Miwa Y, Yamanaka A, Yada T, Shibahara M, Abe Y, Sakurai T, Goto K. (2003) Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins. J Pharmacol Sci, 92: 259-266. [PMID:12890892]


Show »

How to cite this page

Select citation format: