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H4 receptor

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 265

Nomenclature: H4 receptor

Family: Histamine receptors

Contents:

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 7 390 18q11.2 HRH4 histamine receptor H4 2,25-26,28
Mouse 7 391 18 A1 Hrh4 histamine receptor H4 23
Rat 7 391 18p13 Hrh4 histamine receptor H4 23
Previous and Unofficial Names Click here for help
GPCR105 [22] | HH4R [26] | H4R
Database Links Click here for help
Specialist databases
GPCRdb hrh4_human (Hs), hrh4_mouse (Mm), hrh4_rat (Rn)
Other databases
Alphafold Q9H3N8 (Hs), Q91ZY2 (Mm), Q91ZY1 (Rn)
ChEMBL Target CHEMBL3759 (Hs), CHEMBL5657 (Mm), CHEMBL4468 (Rn)
Ensembl Gene ENSG00000134489 (Hs), ENSMUSG00000037346 (Mm), ENSRNOG00000016887 (Rn)
Entrez Gene 59340 (Hs), 225192 (Mm), 170704 (Rn)
Human Protein Atlas ENSG00000134489 (Hs)
KEGG Gene hsa:59340 (Hs), mmu:225192 (Mm), rno:170704 (Rn)
OMIM 606792 (Hs)
Pharos Q9H3N8 (Hs)
RefSeq Nucleotide NM_021624 (Hs), NM_153087 (Mm), NM_131909 (Rn)
RefSeq Protein NP_067637 (Hs), NP_694727 (Mm), NP_571984 (Rn)
UniProtKB Q9H3N8 (Hs), Q91ZY2 (Mm), Q91ZY1 (Rn)
Wikipedia HRH4 (Hs)
Natural/Endogenous Ligands Click here for help
CCL16 {Sp: Human}
histamine

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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]histamine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Full agonist 7.4 – 8.4 pKd 10,22-23,25,28,30
⤷ pKd 7.4 – 8.4 [10,22-23,25,28,30]
N-[3H]methylhistamine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist 7.8 pKd 22
⤷ pKd 7.8 [22]
[125I]CCL16 (human) Peptide Ligand is labelled Ligand is radioactive Hs Full agonist 7.8 pKd 27
⤷ pKd 7.8 [27]
[3H]histamine Small molecule or natural product Ligand is labelled Ligand is radioactive Ligand has a PDB structure Mm Full agonist 7.4 pKd 23
⤷ pKd 7.4 [23]
[3H](R)-α-methylhistamine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist 7.2 pKd 22
⤷ pKd 7.2 [22]
[3H]histamine Small molecule or natural product Ligand is labelled Ligand is radioactive Ligand has a PDB structure Rn Full agonist 6.9 pKd 23
⤷ pKd 6.9 [23]
imetit Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Full agonist 8.2 – 8.9 pKi 22-23,25,44
⤷ pKi 8.2 – 8.9 [22-23,25,44]
imetit Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Mm Full agonist 8.2 pKi 23
⤷ pKi 8.2 [23]
imetit Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Rn Full agonist 8.2 pKi 23
⤷ pKi 8.2 [23]
histamine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Full agonist 7.8 – 8.3 pKi 10,19,22-23,25,39,44
⤷ pKi 7.8 – 8.3 [10,19,22-23,25,39,44]
ST-1006 Small molecule or natural product Click here for species-specific activity table Hs Agonist 7.9 pKi 31
⤷ pKi 7.9 [31]
clobenpropit Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Partial agonist 7.4 – 8.3 pKi 7,19,22-23,25
⤷ pKi 7.4 – 8.3 (Ki 3.98x10-8 – 5.01x10-9 M) [7,19,22-23,25]
clobenpropit Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Mm Partial agonist 7.8 pKi 23
⤷ pKi 7.8 [23]
immepip Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Full agonist 7.6 – 8.0 pKi 16,22,44
⤷ pKi 7.6 – 8.0 [16,22,44]
impromidine Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Partial agonist 7.6 – 7.9 pKi 19,22
⤷ pKi 7.6 – 7.9 [19,22]
4-methylhistamine Small molecule or natural product Hs Full agonist 7.3 – 8.2 pKi 10,19
⤷ pKi 7.3 – 8.2 (Ki 5.01x10-8 – 6.31x10-9 M) [10,19]
VUF 8430 Small molecule or natural product Hs Full agonist 7.5 pKi 18
⤷ pKi 7.5 (Ki 3.16x10-8 M) [18]
N-methylhistamine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.3 – 7.6 pKi 10,22-23
⤷ pKi 7.3 – 7.6 [10,22-23]
histamine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Mm Full agonist 7.4 pKi 23
⤷ pKi 7.4 [23]
histamine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Rn Full agonist 7.2 pKi 23
⤷ pKi 7.2 [23]
clobenpropit Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Rn Partial agonist 7.2 pKi 23
⤷ pKi 7.2 [23]
N-α-methylhistamine Small molecule or natural product Hs Full agonist 6.8 – 7.2 pKi 25,44
⤷ pKi 6.8 – 7.2 [25,44]
(R)-α-methylhistamine Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Full agonist 6.5 – 6.9 pKi 22-23,25,44
⤷ pKi 6.5 – 6.9 [22-23,25,44]
N-ethylhistamine Small molecule or natural product Hs Full agonist 6.7 pKi 10
⤷ pKi 6.7 [10]
N-methylhistamine Small molecule or natural product Mm Full agonist 6.5 pKi 23
⤷ pKi 6.5 [23]
(R)-α-methylhistamine Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Mm Full agonist 6.4 pKi 23
⤷ pKi 6.4 [23]
2-methylhistamine Small molecule or natural product Hs Full agonist 6.1 – 6.6 pKi 10,19
⤷ pKi 6.1 – 6.6 [10,19]
N-methylhistamine Small molecule or natural product Click here for species-specific activity table Rn Full agonist 6.3 pKi 23
⤷ pKi 6.3 [23]
(R)-α-methylhistamine Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Rn Full agonist 6.2 pKi 23
⤷ pKi 6.2 [23]
2-(3-bromophenyl)histamine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 6.0 pKi 19
⤷ pKi 6.0 [19]
N,N-dimethylhistamine Small molecule or natural product Hs Full agonist 5.9 pKi 10
⤷ pKi 5.9 [10]
HTMT Small molecule or natural product Immunopharmacology Ligand Hs Full agonist 5.9 pKi 44
⤷ pKi 5.9 [44]
dimaprit Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.9 – 6.5 pKi 19,22,25,44
⤷ pKi 4.9 – 6.5 [19,22,25,44]
methimepip Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.7 pKi 15
⤷ pKi 5.7 [15]
(S)-α-methylhistamine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.5 pKi 25
⤷ pKi 5.5 [25]
improgan Small molecule or natural product Hs Full agonist 5.2 pKi 44
⤷ pKi 5.2 [44]
CCL16 {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Immunopharmacology Ligand Hs Full agonist 8.1 pIC50 27
⤷ pIC50 8.1 [27]
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]JNJ 7777120 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Antagonist 8.4 pKd 41
⤷ pKd 8.4 (Kd 3.6x10-9 M) [41]
[3H]pyrilamine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 7.5 pKd 28
⤷ pKd 7.5 [28]
adriforant Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 8.3 pKi 31
⤷ pKi 8.3 [31]
INCB-38579 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.3 pKi 31
⤷ pKi 8.3 [31]
JNJ 7777120 Small molecule or natural product Hs Antagonist 7.8 – 8.3 pKi 19,37,41
⤷ pKi 7.8 – 8.3 (Ki 1.58x10-8 – 5.01x10-9 M) [19,37,41]
JNJ-39758979 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 7.9 pKi 31,35
⤷ pKi 7.9 (Ki 1.25x10-8 M) [31,35]
iodophenpropit Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.7 pKi 44
⤷ pKi 7.7 [44]
thioperamide Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Mm Antagonist 7.6 pKi 23
⤷ pKi 7.6 [23]
thioperamide Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Antagonist 7.6 pKi 23
⤷ pKi 7.6 [23]
JNJ-10191584 Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 7.1 pKi 39
⤷ pKi 7.1 [39]
toreforant Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 7.1 pKi 5
⤷ pKi 7.1 (Ki 8.3x10-8 M) [5]
Description: Displacament of histamine from human H4 recepotor expressed in mammalian cells.
burimamide Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.7 – 7.4 pKi 19,22-23,25,44
⤷ pKi 6.7 – 7.4 [19,22-23,25,44]
thioperamide Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 6.3 – 7.6 pKi 6-7,22-23,25,44
⤷ pKi 6.3 – 7.6 Selective for H3/H4 compared to H1 and H3. [6-7,22-23,25,44]
clozapine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 6.2 – 6.7 pKi 19,22-23,44
⤷ pKi 6.2 – 6.7 [19,22-23,44]
burimamide Small molecule or natural product Mm Antagonist 6.1 pKi 23
⤷ pKi 6.1 [23]
burimamide Small molecule or natural product Click here for species-specific activity table Rn Antagonist 6.0 pKi 23
⤷ pKi 6.0 [23]
ciproxifan Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.7 pKi 6-7,31
⤷ pKi 5.7 [6-7,31]
clozapine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 5.7 pKi 23
⤷ pKi 5.7 [23]
clozapine Small molecule or natural product Approved drug Click here for species-specific activity table Mm Antagonist 5.5 pKi 23
⤷ pKi 5.5 [23]
MK-0249 Small molecule or natural product Click here for species-specific activity table Hs Antagonist <5.0 pKi 31
⤷ pKi <5.0 (Ki >1x10-5 M) [31]
conessine Small molecule or natural product Click here for species-specific activity table Hs Antagonist <5.0 pKi 31
⤷ pKi <5.0 (Ki >1x10-5 M) [31]
pitolisant Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist <4.0 pKi 31
⤷ pKi <4.0 (Ki >1x10-4 M) [31]
H4 antagonist 48 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Antagonist 7.6 pIC50 17
⤷ pIC50 7.6 (IC50 2.7x10-8 M) [17]
Description: Radioligand competitive binding assay using [3H]Histamine as tracer, and membrane preparations from CHO-K1 cells expressing human H4 receptor.
H4 antagonist 48 Small molecule or natural product Immunopharmacology Ligand Mm Antagonist 6.5 pIC50 17
⤷ pIC50 6.5 (IC50 2.9x10-7 M) [17]
Description: Radioligand competitive binding assay using [3H]Histamine as tracer, and membrane preparations from CHO-K1 cells expressing mouse H4 receptor.
SENS-111 Small molecule or natural product Hs Antagonist - - 33
⤷ [33]
View species-specific antagonist tables
Antagonist Comments
H4 antagonist 48 exhibits no appreciable binding to the H1, H2 or H3 receptors (IC50s >10 μM) [17].
Immunopharmacology Comments
H4 receptor is primarily expressed in mast cells and eosinophils, but is also found on human neutrophils and basophils, and plays an important role in modulating eosinophil chemotaxis [29,43]. H4 receptor acts in concert with H2 receptor to enhance IL-16 production in lymphocytes [32]. In mast cells, selective H4 receptor activation increases calcium influx, degranulation, cytokine release and leukotriene production (cysteinyl and LTB4) [14]. In comparison to the H1 receptor, the H4 receptor is a relatively new therapeutic target for inflammation [3,8,40]. Selective H4 receptor antagonists are in development for potential clinical use, in particular for the treatment of Th2-dependent dermal inflammation such as atopic dermatitis (see for example H4 antagonist 48), and asthma [12]. Novartis' lead H4 antagonist adriforant is in Phase 2 evaluation as of November 2018, in patients with psoriasis and atopic dermatitis [42].
Cell Type Associations
Immuno Cell Type:  Granulocytes
Cell Ontology Term:   eosinophil (CL:0000771)
Comment:  Eosinophils express all four histamine receptor subtypes.
References:  11,24
Immuno Cell Type:  Mast cells
Cell Ontology Term:   mast cell (CL:0000097)
Comment:  In humans, mast cells express H1R, H2R and H4R.
References:  9
Immuno Process Associations
Immuno Process:  Inflammation
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Phospholipase C stimulation
References:  13
Tissue Distribution Click here for help
Gastrointestinal tract.
Species:  Human
Technique:  qRT-PCR and immunohistochemistry.
References:  34
Eosinophils.
Species:  Human
Technique:  Northern blotting.
References:  22
Monocytes.
Species:  Human
Technique:  Flow cytometry.
References:  4
Bone marrow and spleen.
Species:  Human
Technique:  RNase protection assay.
References:  22
Leukocyte, spleen, lung, liver > heart, skeletal muscle.
Brain: cerebellum, hippocampus.
Species:  Human
Technique:  RT-PCR.
References:  2
Eosinophils.
Species:  Human
Technique:  RT-PCR.
References:  27
Mast cells.
Species:  Human
Technique:  RT-PCR.
References:  21
Peripheral blood leukocytes, thymus, small intestine, spleen, and colon.
Species:  Human
Technique:  RT-PCR.
References:  30
Eosinophils and dendritic cells.
Species:  Human
Technique:  RT-PCR.
References:  20
Mast cells and eosinophils.
Species:  Mouse
Technique:  RT-PCR and Northern Blotting.
References:  13
Eosinophils.
Species:  Mouse
Technique:  RT-PCR.
References:  27
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
Measurement of cAMP levels in SK-N-MC cells transfected with the human H4 receptor using a cAMP-sensitive reporter gene.
Species:  Human
Tissue:  SK-N-MC cells.
Response measured:  Inhibition of cAMP accumulation.
References:  19,22-23
Measurement of Ca2+ levels in mouse mast cells endogenously expressing the H4 receptor.
Species:  Mouse
Tissue:  Mast cells.
Response measured:  Ca2+ mobilisation from intracellular stores.
References:  13
Measurement of cAMP levels in HEK 293 cells transfected with the human H4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  10,26
Measurement of Ca2+ levels in HEK 293 cells transfected with the human H4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Ca2+ mobilisation.
References:  25,36
Measurement of MAPK activity in HEK 293 cells transfected with the human H4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Stimulation of MAPK activity.
References:  25
Measurement of Ca2+ levels in human monocytes endogenously expressing the H4 receptor.
Species:  Human
Tissue:  Monocytes.
Response measured:  Stimulation of Ca2+ mobilisation.
References:  4
Physiological Functions Click here for help
Eosinophil shape change.
Species:  Human
Tissue:  Eosinophils.
References:  1,20
Upregulation of cell surface adhesion molecules.
Species:  Human
Tissue:  Eosinophils.
References:  20
Chemotaxis.
Species:  Human
Tissue:  Eosinophils.
References:  20
Chemotaxis.
Species:  Mouse
Tissue:  Mast cells.
References:  13
Eosinophil trafficking.
Species:  Mouse
Tissue:  In vivo.
References:  27
Zymosan-induced neutrophil release from bone marrow.
Species:  Mouse
Tissue:  In vivo.
References:  38
Inhibition of CCL2 production.
Species:  Human
Tissue:  Monocytes.
References:  4
Physiological Consequences of Altering Gene Expression Click here for help
Chemotaxis is not seen in mast cells from H4 receptor knockout mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  13
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
Hrh4tm1Lex Hrh4tm1Lex/Hrh4tm1Lex
involves: 129S/SvEv * BALB/c		 MGI:2429635  MP:0008721 abnormal chemokine level PMID: 16709868 
Hrh4tm1Lex Hrh4tm1Lex/Hrh4tm1Lex
involves: 129S/SvEv * BALB/c		 MGI:2429635  MP:0002376 abnormal dendritic cell physiology PMID: 16709868 
Hrh4tm1Lex Hrh4tm1Lex/Hrh4tm1Lex
involves: 129S/SvEv * BALB/c		 MGI:2429635  MP:0008751 abnormal interleukin level PMID: 16709868 
Hrh4tm1Lex Hrh4tm1Lex/Hrh4tm1Lex
involves: 129S/SvEv * C57BL/6		 MGI:2429635  MP:0002423 abnormal mast cell physiology PMID: 16709868 
Hrh4+|Hrh4tm1Lex Hrh4tm1Lex/Hrh4+
involves: 129S/SvEv * C57BL/6		 MGI:2429635  MP:0002423 abnormal mast cell physiology PMID: 12626656 
Hrh4tm1Lex Hrh4tm1Lex/Hrh4tm1Lex
involves: 129S/SvEv * BALB/c		 MGI:2429635  MP:0002492 decreased IgE level PMID: 16709868 
Hrh4tm1Lex Hrh4tm1Lex/Hrh4tm1Lex
involves: 129S/SvEv * BALB/c		 MGI:2429635  MP:0008495 decreased IgG1 level PMID: 16709868 
Hrh4tm1Lex Hrh4tm1Lex/Hrh4tm1Lex
involves: 129S/SvEv * BALB/c		 MGI:2429635  MP:0001876 decreased inflammatory response PMID: 16709868 

References

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1. Buckland KF, Williams TJ, Conroy DM. (2003) Histamine induces cytoskeletal changes in human eosinophils via the H(4) receptor. Br J Pharmacol, 140 (6): 1117-27. [PMID:14530216]

2. Cogé F, Guénin SP, Rique H, Boutin JA, Galizzi JP. (2001) Structure and expression of the human histamine H4-receptor gene. Biochem Biophys Res Commun, 284 (2): 301-9. [PMID:11394877]

3. de Esch IJ, Thurmond RL, Jongejan A, Leurs R. (2005) The histamine H4 receptor as a new therapeutic target for inflammation. Trends Pharmacol Sci, 26 (9): 462-9. [PMID:16054239]

4. Dijkstra D, Leurs R, Chazot P, Shenton FC, Stark H, Werfel T, Gutzmer R. (2007) Histamine downregulates monocyte CCL2 production through the histamine H4 receptor. J Allergy Clin Immunol, 120 (2): 300-7. [PMID:17507084]

5. Edwards JP, Kindrachuk DE, Venable JD, Mapes CM, Pippel DJ,. (2007) Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H4 receptor. Patent number: WO2007117399. Assignee: Janssen Pharmaceutica Nv. Priority date: 31/03/2006. Publication date: 18/10/2007.

6. Esbenshade TA, Fox GB, Krueger KM, Baranowski JL, Miller TR, Kang CH, Denny LI, Witte DG, Yao BB, Pan JB et al.. (2004) Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist. Biochem Pharmacol, 68 (5): 933-45. [PMID:15294456]

7. Esbenshade TA, Krueger KM, Miller TR, Kang CH, Denny LI, Witte DG, Yao BB, Fox GB, Faghih R, Bennani YL et al.. (2003) Two novel and selective nonimidazole histamine H3 receptor antagonists A-304121 and A-317920: I. In vitro pharmacological effects. J Pharmacol Exp Ther, 305 (3): 887-96. [PMID:12606603]

8. Fung-Leung WP, Thurmond RL, Ling P, Karlsson L. (2004) Histamine H4 receptor antagonists: the new antihistamines?. Curr Opin Investig Drugs, 5 (11): 1174-83. [PMID:15573868]

9. Gangwar RS, Landolina N, Arpinati L, Levi-Schaffer F. (2017) Mast cell and eosinophil surface receptors as targets for anti-allergic therapy. Pharmacol Ther, 170: 37-63. [PMID:27773785]

10. Gbahou F, Vincent L, Humbert-Claude M, Tardivel-Lacombe J, Chabret C, Arrang JM. (2006) Compared pharmacology of human histamine H3 and H4 receptors: structure-activity relationships of histamine derivatives. Br J Pharmacol, 147 (7): 744-54. [PMID:16432504]

11. Gibbs BF, Levi-Schaffer F. (2012) H₄ receptors in mast cells and basophils: a new therapeutic target for allergy?. Front Biosci (Landmark Ed), 17: 430-7. [PMID:22201753]

12. Hartwig C, Munder A, Glage S, Wedekind D, Schenk H, Seifert R, Neumann D. (2015) The histamine H4 -receptor (H4 R) regulates eosinophilic inflammation in ovalbumin-induced experimental allergic asthma in mice. Eur J Immunol, 45 (4): 1129-40. [PMID:25501767]

13. Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP. (2003) Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. J Pharmacol Exp Ther, 305 (3): 1212-21. [PMID:12626656]

14. Jemima EA, Prema A, Thangam EB. (2014) Functional characterization of histamine H4 receptor on human mast cells. Mol Immunol, 62 (1): 19-28. [PMID:24934979]

15. Kitbunnadaj R, Hashimoto T, Poli E, Zuiderveld OP, Menozzi A, Hidaka R, de Esch IJ, Bakker RA, Menge WM, Yamatodani A et al.. (2005) N-substituted piperidinyl alkyl imidazoles: discovery of methimepip as a potent and selective histamine H3 receptor agonist. J Med Chem, 48 (6): 2100-7. [PMID:15771452]

16. Kitbunnadaj R, Zuiderveld OP, De Esch IJ, Vollinga RC, Bakker R, Lutz M, Spek AL, Cavoy E, Deltent MF, Menge WM et al.. (2003) Synthesis and structure-activity relationships of conformationally constrained histamine H(3) receptor agonists. J Med Chem, 46 (25): 5445-57. [PMID:14640553]

17. Ko K, Kim HJ, Ho PS, Lee SO, Lee JE, Min CR, Kim YC, Yoon JH, Park EJ, Kwon YJ et al.. (2018) Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis. J Med Chem, 61 (7): 2949-2961. [PMID:29579390]

18. Lim HD, Smits RA, Bakker RA, van Dam CM, de Esch IJ, Leurs R. (2006) Discovery of S-(2-guanidylethyl)-isothiourea (VUF 8430) as a potent nonimidazole histamine H4 receptor agonist. J Med Chem, 49 (23): 6650-1. [PMID:17154494]

19. Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R. (2005) Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. J Pharmacol Exp Ther, 314 (3): 1310-21. [PMID:15947036]

20. Ling P, Ngo K, Nguyen S, Thurmond RL, Edwards JP, Karlsson L, Fung-Leung WP. (2004) Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation. Br J Pharmacol, 142 (1): 161-71. [PMID:15131002]

21. Lippert U, Artuc M, Grützkau A, Babina M, Guhl S, Haase I, Blaschke V, Zachmann K, Knosalla M, Middel P et al.. (2004) Human skin mast cells express H2 and H4, but not H3 receptors. J Invest Dermatol, 123 (1): 116-23. [PMID:15191551]

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