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OX2 receptor

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Target not currently curated in GtoImmuPdb

Target id: 322

Nomenclature: OX2 receptor

Family: Orexin receptors

Gene and Protein Information Click here for help
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 55
Mouse 7 460 9q-D Hcrtr2 hypocretin (orexin) receptor 2 13,55
Rat 7 460 8q24 Hcrtr2 hypocretin receptor 2 55
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 Click here for help
hypocretin receptor 2 | orexin receptor type 2 | OX2R
Database Links Click here for help
Specialist databases
GPCRDB ox2r_human (Hs), ox2r_mouse (Mm), ox2r_rat (Rn)
Other databases
Alphafold
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structures of human orexin 2 receptor bound to the selective antagonist EMPA determined by serial femtosecond crystallography at SACLA
PDB Id:  5WS3
Ligand:  EMPA
Resolution:  2.3Å
Species:  Human
References:  59
Image of receptor 3D structure from RCSB PDB
Description:  Orexin Receptor 2 (OX2R) in Complex with G Protein and Natural Peptide-Agonist Orexin B (OxB)
PDB Id:  7L1U
Ligand:  orexin-B
Resolution:  3.2Å
Species:  Human
References:  27
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human OX2 orexin receptor bound to the insomnia drug Suvorexant
PDB Id:  4S0V
Ligand:  suvorexant
Resolution:  2.5Å
Species:  Human
References:  68
Image of receptor 3D structure from RCSB PDB
Description:  Orexin Receptor 2 (OX2R) in Complex with G Protein and Small-Molecule Agonist Compound 1
PDB Id:  7L1V
Ligand:  compound 1 [PMID: 33547286]
Resolution:  3.0Å
Species:  Human
References:  27
Natural/Endogenous Ligands Click here for help
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)

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]T-516 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Agonist 7.3 pKd 70
pKd 7.3 (Kd 4.8x10-8 M) [70]
Description: Determined in a radioligand binding assay using membrane fractions from hOX2R-transfected Expi293F cells.
[Ala11, D-Leu15]orexin-B Peptide Click here for species-specific activity table Hs Full agonist 7.6 – 9.9 pEC50 3,49
pEC50 7.6 – 9.9 [3,49]
[3H]T-516 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Full agonist 8.4 pEC50 70
pEC50 8.4 (EC50 4.3x10-9 M) [70]
Description: Determined in a calcium mobilization assay
compound 1 [PMID: 33547286] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 8.3 pEC50 27
pEC50 8.3 [27]
TAK-925 Small molecule or natural product Ligand has a PDB structure Hs Full agonist 8.3 pEC50 70
pEC50 8.3 (EC50 5.5x10-9 M) [70]
Description: Measuring TAK-925-induced calcium mobilization in hOX2R/CHO-K1 cells
orexin-A {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 6.5 – 10.0 pEC50 2,23,25,31-32,46,55,57,61
pEC50 6.5 – 10.0 [2,23,25,31-32,46,55,57,61]
orexin-B {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 6.5 – 10.0 pEC50 2,23,25,46,55,57,61
pEC50 6.5 – 10.0 [2,23,25,46,55,57,61]
YNT-185 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.6 pEC50 28,44,52
pEC50 7.6 (EC50 2.8x10-8 M) [28,44,52]
Nag 26 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Agonist 5.2 – 7.8 pEC50 28,44,52
pEC50 5.2 – 7.8 (EC50 6.31x10-6 – 1.58x10-8 M) [28,44,52]
[125I]-orexin-A Peptide Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Agonist - - 32,48,55
Useful working concentration sub nM-low nM. [32,48,55]
Agonist Comments
Efficacy and potency values for agonists are highly dependent on cell type, assay conditions and the readout.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]-almorexant Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 8.9 – 9.8 pKd 39-40
pKd 8.9 – 9.8 (Kd 1.25x10-9 – 1.58x10-10 M) [39-40]
[3H]Cp-1 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Antagonist 9.2 – 9.4 pKd 39
pKd 9.2 – 9.4 (Kd 6.3x10-10 – 4x10-10 M) [39]
[3H]-TCS 1102 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 9.0 pKd 12
pKd 9.0 (Kd 1x10-9 M) [12]
[3H]EMPA Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Antagonist 8.6 – 9.0 pKd 38,40
pKd 8.6 – 9.0 (Kd 2.51x10-9 – 1x10-9 M) [38,40]
[3H]SB-674042 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 6.9 pKd 35,39
pKd 6.9 [35,39]
TCS 1102 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.7 pKi 5
pKi 9.7 (Ki 2x10-10 M) [5]
SB-649868 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.9 – 9.8 pKi 12,16
pKi 8.9 – 9.8 [12,16]
MK-1064 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.3 pKi 53
pKi 9.3 (Ki 5x10-10 M) [53]
suvorexant Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.9 – 9.5 pKi 12,16,43
pKi 8.9 – 9.5 [12,16,43]
filorexant Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.9 – 9.1 pKi 12,16,66
pKi 8.9 – 9.1 [12,16,66]
MK-3697 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.0 pKi 54
pKi 9.0 (Ki 1.1x10-9 M) [54]
Cp-1 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.5 – 9.3 pKi 38-39
pKi 8.5 – 9.3 [38-39]
EMPA Small molecule or natural product Ligand has a PDB structure Hs Antagonist 8.4 – 9.2 pKi 38-40,43,62
pKi 8.4 – 9.2 300–3000-fold selective [38-40,43,62]
HTL6641 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.6 pKi 14
pKi 8.6 (Ki 2.5x10-9 M) [14]
lemborexant Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.5 pKi 69
pKi 8.5 (Ki 3x10-9 M) [69]
Description: In vitro radioligand binding assay
LSN2424100 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.4 pKi 20
pKi 8.4 (Ki 4.5x10-9 M) [20]
compound 11 [PMID: 15261275] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.3 pKi 41
pKi 8.3 (Ki 5.01x10-9 M) [41]
Description: Radioligand displacement assay using [125I]-orexin A as radio ligand.
seltorexant Small molecule or natural product Click here for species-specific activity table Rn Antagonist 8.1 pKi 7
pKi 8.1 (Ki 7.9x10-9 M) [7]
Description: In vitro radioligand binding assay
JNJ-10397049 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.7 – 8.4 pKi 16,41,62
pKi 7.7 – 8.4 200–800-fold selective [16,41,62]
seltorexant Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.0 pKi 7
pKi 8.0 (Ki 1x10-8 M) [7]
Description: In vitro radioligand binding assay
JH112 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.3 pKi 21
pKi 7.3 (Ki 5.4x10-8 M) [21]
TCS-OX2-29 Small molecule or natural product Hs Antagonist 6.9 – 7.5 pKi 22,43
pKi 6.9 – 7.5 [22,43]
compound 1 [PMID: 15261275] Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.8 – 7.1 pKi 41
pKi 6.8 – 7.1 [41]
SB-674042 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 6.9 pKi 35
pKi 6.9 (Ki 1.29x10-7 M) [35]
SB-408124 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 5.7 – 6.0 pKi 35,39,43
pKi 5.7 – 6.0 [35,39,43]
SB-334867 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 5.2 – 6.3 pKi 39,43,47
pKi 5.2 – 6.3 [39,43,47]
almorexant Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.0 – 8.1 pIC50 9,43
pIC50 8.0 – 8.1 (IC50 1x10-8 – 7.94x10-9 M) [9,43]
ACT-462206 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.0 pIC50 8
pIC50 8.0 (IC50 1.1x10-8 M) [8]
ACT-335827 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.3 – 6.6 pIC50 58
pIC50 6.3 – 6.6 (IC50 4.71x10-7 – 2.71x10-7 M) [58]
ACT-335827 Small molecule or natural product Click here for species-specific activity table Rn Antagonist 6.0 – 6.2 pIC50 58
pIC50 6.0 – 6.2 (IC50 1.03x10-6 – 6.3x10-7 M) [58]
View species-specific antagonist tables
Primary Transduction Mechanisms Click here for help
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:  2,17,23,25,30-34,36,51,55,61
Tissue Distribution Click here for help
Pituitary: corticotroph cells.
Species:  Human
Technique:  Immunohistochemistry
References:  6
Lymph node > bone marrow, spleen > thymus > lung > liver > kidney > spinal cord.
Species:  Mouse
Technique:  RT-PCR
References:  26
OX: brain, lung, spleen, testis.
OX: skeletal muscle, testis, spleen > brain, lung > liver, kidney.
Species:  Mouse
Technique:  PCR
References:  13
CNS: highest levels found in the brainstem, hypothalamus, thalamus > dorsal root ganglia.
Species:  Rat
Technique:  RT-PCR
References:  15
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:  63
Tuberomammillary (TM) neurons in the hypothalamus.
Species:  Rat
Technique:  RT-PCR
References:  19
Pancreatic islets.
Species:  Rat
Technique:  RT-PCR
References:  45
Brainstem: lateral reticular field (LRt) and the nucleus of the solitary tract (NTS).
Species:  Rat
Technique:  in situ hybridisation
References:  60
Adrenal medulla.
Species:  Rat
Technique:  RT-PCR and immunohistrochemistry
References:  37
Pineal gland.
Species:  Rat
Technique:  RT-PCR
References:  42
CNS: highest levels found in the cerebral neocortex, basal ganglia, hippocampal formation, hypothalamus, thalamus, midbrain, reticular formation.
Species:  Rat
Technique:  Immunohistochemistry
References:  15
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
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 Click here for help

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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]

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Functional Assays Click here for help
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:  49,61
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:  23
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:  71
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:  2,24,31-32,55,57
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:  23
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:  64
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:  31-32
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:  61
Physiological Functions Click here for help
Stimulation of food intake.
Species:  Rat
Tissue:  In vivo.
References:  55
Excitation of neurons known to contribute to wakefulness.
Species:  Rat
Tissue:  Tuberomammillary (TM) nuclei from histaminergic neurons..
References:  4,19
Excitation of GABAergic neurons.
Species:  Rat
Tissue:  Septohippocampal GABAergic neurons.
References:  67
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:  29
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:  42
Excitation of neurons known to contribute to wakefulness.
Species:  Rat
Tissue:  Basal forebrain (BF) cholinergic neurons.
References:  18
Ethanol induced self-administration, place preference and behavioral reinstatement blocked by selective OX2 receptor antagonist, JNJ-10397049
Species:  Rat
Tissue:  Systemic (subcutaneous administration)
References:  56
Physiological Consequences of Altering Gene Expression Click here for help
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
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  65
Physiological Consequences of Altering Gene Expression Comments
Hcrtr2 gene disruption does not appear to result in physiological problems.
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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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 Click here for help
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:  50

References

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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. 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. 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

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

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