HRH4

Summary

HRH4 (histamine receptor H4, HGNC:17383) is a protein-coding gene on chromosome 18q11.2, encoding Histamine H4 receptor (Q9H3N8). G protein-coupled receptor primarily expressed in immune cells such as mast cells, eosinophils, basophils, dendritic cells and neutrophils that plays a key role in immune and inflammatory responses.

Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by a family of histamine receptors, which are a subset of the G-protein coupled receptor superfamily. This gene encodes a histamine receptor that is predominantly expressed in haematopoietic cells. The protein is thought to play a role in inflammation and allergy reponses. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 59340 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 62 total
• Druggable target: yes — 18 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_021624

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17383
Approved symbol	HRH4
Name	histamine receptor H4
Location	18q11.2
Locus type	gene with protein product
Status	Approved
Aliases	H4R, HH4R, AXOR35, GPCR105, GPRv53
Ensembl gene	ENSG00000134489
Ensembl biotype	protein_coding
OMIM	606792
Entrez	59340

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000256906, ENST00000426880

RefSeq mRNA: 3 — MANE Select: NM_021624 NM_001143828, NM_001160166, NM_021624

CCDS: CCDS11887, CCDS45841

Canonical transcript exons

ENST00000256906 — 3 exons

Exon	Start	End
ENSE00000915336	24468788	24468951
ENSE00001145758	24460637	24460921
ENSE00001229484	24476747	24479961

Expression profiles

Bgee: expression breadth broad, 50 present calls, max score 61.38.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3336 / max 59.2146, expressed in 59 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169743	0.2939	59
169744	0.0397	19

Top tissues by expression

232 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	61.38	gold quality
mononuclear cell	CL:0000842	61.24	gold quality
leukocyte	CL:0000738	61.01	gold quality
bone marrow	UBERON:0002371	57.28	gold quality
decidua	UBERON:0002450	56.55	gold quality
bone marrow cell	CL:0002092	56.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	55.40	gold quality
tibialis anterior	UBERON:0001385	54.36	silver quality
blood	UBERON:0000178	53.75	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
cranial nerve II	UBERON:0000941	51.35	silver quality
vermiform appendix	UBERON:0001154	50.88	gold quality
ileal mucosa	UBERON:0000331	50.81	silver quality
deltoid	UBERON:0001476	50.73	silver quality
caecum	UBERON:0001153	49.56	gold quality
buccal mucosa cell	CL:0002336	49.37	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
quadriceps femoris	UBERON:0001377	49.22	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
epithelial cell of pancreas	CL:0000083	48.59	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
vastus lateralis	UBERON:0001379	48.25	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.10

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KMT2B, PAX1

miRNA regulators (miRDB)

105 targeting HRH4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975

Literature-anchored findings (GeneRIF, showing 40)

• human mast cells constitutively express primarily H2 and H4 receptors (PMID:15191551)
• Human eosinophils express H4. CCL16 is a novel functional ligand for H4, and it induced efficient migratory responses in human eosinophils. (PMID:15265943)
• histamine exerts both a proproliferative and a proangiogenic effect via H2/H4 receptor activation, mediated by increasing COX-2-related PGE2 production in COX-2-expressing colon cancer cells (PMID:16203768)
• results showed for the first time the presence of histamine h4 receptor protein in epithelial cells of human normal mammary gland (PMID:16547802)
• STAT6 binding to STAT6 promotor gene was regulated by H4 receptor-induced signal transduction and/or cross talk particularly in atopic human lymphocytes ex vivo (PMID:16547812)
• The H(4)R could represent an important anti-inflammatory receptor on monocytes and could be an interesting target for drug development. (PMID:17507084)
• Histamine excites human enteric neurones and this effect involves histamine H1-4 receptors. (PMID:17627982)
• H4 histamine receptor mediates optimal migration of mast cell precursors to CXCL12 and plays a role in the perpetuation of allergic response. (PMID:17681365)
• Results describe the expression of histamine H4 receptors in normal placentas and in placentas from pregnancies complicated by pregestational diabetes. (PMID:17806168)
• Results describe the distribution pattern of histamine H4 receptor in human synovial tissue in patients with rheumaoid arthritis. (PMID:17806182)
• Expression of histamine H4 receptor in synovial cells from rheumatoid arthritis patients is reported. (PMID:17978505)
• Inflammatory dendritic epidermal cells express a functionally active H(4)R, which upon stimulation leads to downregulation of CCL2 and IL-12. (PMID:18239617)
• a dramatic alteration in the distribution of histamine receptors in colon cancer (PMID:18258331)
• Results describe the expression of the histamine H4 receptor in human synovial cells. (PMID:18345487)
• Data suggest that histamine receptor H4R-selective ligands influence the STAT6 transcription activation domain and DNA-binding. (PMID:18345495)
• Data show that histamine regulates pancreatic carcinoma cell growth through H3 and H4 receptors. (PMID:18345506)
• Recombinant histamine 4 receptor (H4R) splice variants derived from cord blood cells have a dominant negative effect on functionality, as these H4R are retained intracellularly and inactivate a population of H4R, presumably via hetero-oligomerization. (PMID:18452403)
• Molecular dynamics (MD) simulations in a membrane-embedded environment were carried out on the homology model of the human histamine H4 receptor (PMID:18572901)
• GIRK channels represent a novel effector system for histamine H(4) receptor modulation (PMID:18582456)
• Phenylalanine 169 in the second extracellular loop of the human histamine H4 receptor is responsible for the difference in agonist binding between human and mouse H4 receptors. (PMID:18635748)
• findings show that transcripts of H(4) receptor are present in all analyzed regions of the central nervous system, including spinal cord, hippocampus, cortex, thalamus & amygdala, with the highest levels of H(4) mRNA detected in the spinal cord (PMID:19046950)
• analysis of how quinazolines can act as histamine H4 receptor inverse agonists (PMID:19053770)
• hH(4)R shows high constitutive activity and structural instability and hH(4)R shows a G-protein-independent high-affinity state. (PMID:19166345)
• Data describe the ultrastructure of the choroid plexus, the number of mast cells that may infiltrate it, and the immunodistribution of histamine receptors H4 and histamine-releasing factor. (PMID:19271148)
• Human CD4(+) T cells express a functional H(4)R. The receptor is upregulated under T(H)2 conditions, and its stimulation leads to induction of AP-1 and IL-31. (PMID:19281909)
• show that progenitor cell populations express this receptor subtype on transcriptional and protein levels and respond to its agonists by reduced growth factor-induced cell cycle progression that leads to decreased myeloid, erythroid and lymphoid formation (PMID:19662098)
• Langerhans cells express a functional H(4)R and point towards a possible pathogenic relevance of the H(4)R in inflammatory and allergic diseases. (PMID:19958313)
• Data reveal that the sulfonamide analogues have excellent H(4)R affinity and behave as inverse agonists at the human H(4)R. (PMID:20192225)
• Polymorphisms of ss142022671, ss142022677 and ss142022679 in HRH4 are associated with atopic dermatitis. (PMID:20199554)
• Copy number variations of the human histamine H4 receptor gene are associated with systemic lupus erythematosus (PMID:20618322)
• slan-dendritic cells (slanDC) express the H(4) R and its stimulation leads to reduced pro-inflammatory capacity of slanDC (PMID:20722760)
• we describe a possible genetic impact on the expression level of the histamine H4 receptor and summarize the current data regarding the activity of the histamine H4 receptor on the key effector cells in atopic dermatitis (PMID:21104170)
• Histamine H4 receptors were found in normal nasal mucosa, and increased significantly in nasal mucosa of allergic rhinitis patients. (PMID:21171298)
• These findings suggested a potential role of abnormal HRH4 expression in the progression of CRCs (PMID:21609450)
• our results indicate that the H(4)R is highly expressed on plasmacytoid dendritic cells in psoriasis and influences cytokine production and migration of these cells (PMID:21614010)
• histamine H(4) receptor as an attractive target in the treatment of inflammatory and autoimmune disorders (PMID:21741967)
• Report down-regulation of HRH4 mRNA in synovial tissue from rheumatoid arthritis patients compared to those with osteoarthritis. (PMID:21881994)
• Histamine receptor-4-mRNA expression showed a significant increase in caudate nucleus and putamen in Parkinson’s disease patients. (PMID:22118942)
• analysis of fragment optimization and analysis of binding kinetics for ligand based design of novel histamine H receptor antagonists (PMID:22153663)
• fundamental concepts of HR structure modeling and its implementation in drug discovery (review) (PMID:22201741)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hrh4	ENSMUSG00000037346
rattus_norvegicus	Hrh4	ENSRNOG00000016887

Paralogs (25): DRD4 (ENSG00000069696), HRH3 (ENSG00000101180), HRH2 (ENSG00000113749), CHRM3 (ENSG00000133019), TAAR5 (ENSG00000135569), GPR84 (ENSG00000139572), GPR161 (ENSG00000143147), TAAR2 (ENSG00000146378), TAAR6 (ENSG00000146383), TAAR8 (ENSG00000146385), TAAR1 (ENSG00000146399), DRD3 (ENSG00000151577), HTR4 (ENSG00000164270), CHRM1 (ENSG00000168539), DRD5 (ENSG00000169676), HTR1A (ENSG00000178394), HTR1D (ENSG00000179546), CHRM4 (ENSG00000180720), CHRM2 (ENSG00000181072), DRD1 (ENSG00000184845), CHRM5 (ENSG00000184984), GPR21 (ENSG00000188394), HRH1 (ENSG00000196639), GPR52 (ENSG00000203737), TAAR9 (ENSG00000237110)

Protein

Protein identifiers

Histamine H4 receptor — Q9H3N8 (reviewed: Q9H3N8)

Alternative names: AXOR35, G-protein coupled receptor 105, GPRv53, Pfi-013, SP9144

All UniProt accessions (1): Q9H3N8

UniProt curated annotations — full annotation on UniProt →

Function. G protein-coupled receptor primarily expressed in immune cells such as mast cells, eosinophils, basophils, dendritic cells and neutrophils that plays a key role in immune and inflammatory responses. Mediates chemotaxis of immune cells to sites of inflammation or injury by responding to histamine. Activation by histamine also influences the release of proinflammatory cytokines such as TNF, CCL4, IL6 and IFN-gamma. Ligand binding induces a conformation change that triggers signaling via G(i)/GNAI1 leading to decreased intracellular cAMP levels by inhibiting adenylate cyclase activity. In addition, plays a role in the control of renal reabsorption processes, particularly albumin uptake.

Subunit / interactions. Interacts with TSPAN4. Interacts with GNAI1.

Subcellular location. Cell membrane.

Tissue specificity. Expressed primarily in the bone marrow and eosinophils. Shows preferential distribution in cells of immunological relevance such as T-cells, dendritic cells, monocytes, mast cells, neutrophils and basophils. Also expressed in a wide variety of peripheral tissues, including the heart, kidney, liver, lung, pancreas, skeletal muscle, prostate, small intestine, spleen, testis, colon, fetal liver and lymph node.

Induction. Expression is either up-regulated or down-regulated upon activation of the lymphoid tissues and this regulation may depend on the presence of IL10/interleukin-10 or IL13/interleukin-13.

Miscellaneous. Does not bind diphenhydramine, loratadine, ranitidine, cimetidine and chlorpheniramine. Shows modest affinity for dimaprit, impromidine, clobenpropit, thioperamide, burimamide clozapine, immepip and imetit. The order of inhibitory activity was imetit > clobenpropit > burimamide > thioperamide. Clobenpropit behaves as a partial agonist, dimaprit and impromidine show some agonist activity while clozapine behaves as a full agonist. Thioperamide shows inverse agonism (enhances cAMP activity). The order of inhibitory activity of histamine derivatives was Histamine > N-alpha-methylhistamine > R(-)-alpha-methylhistamine > S(+)-alpha-methylhistamine. Both N-alpha-methylhistamine > R(-)-alpha-methylhistamine behave as full agonists.

Similarity. Belongs to the G-protein coupled receptor 1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H3N8-1	1	yes
Q9H3N8-2	2

RefSeq proteins (3): NP_001137300, NP_001153638, NP_067637* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR008102	Histamine_H4_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (43 total): helix 13, topological domain 8, transmembrane region 7, strand 3, glycosylation site 2, sequence variant 2, mutagenesis site 2, turn 2, chain 1, disulfide bond 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
8YN9	ELECTRON MICROSCOPY	2.3
9JED	ELECTRON MICROSCOPY	2.58
8YNA	ELECTRON MICROSCOPY	2.63
9LRC	ELECTRON MICROSCOPY	2.84
9LRE	ELECTRON MICROSCOPY	2.84
9L42	ELECTRON MICROSCOPY	2.9
7YFC	ELECTRON MICROSCOPY	3
8HN8	ELECTRON MICROSCOPY	3
8HOC	ELECTRON MICROSCOPY	3
8JXW	ELECTRON MICROSCOPY	3.01
8JXX	ELECTRON MICROSCOPY	3.06
8JXT	ELECTRON MICROSCOPY	3.07
7YFD	ELECTRON MICROSCOPY	3.1
8JXV	ELECTRON MICROSCOPY	3.21
9JG1	ELECTRON MICROSCOPY	3.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3N8-F1	76.93	0.39

Antibody-complex structures (SAbDab): 12 — 7YFC, 7YFD, 8HN8, 8HOC, 8JXT, 8JXV, 8JXW, 8JXX, 8YN9, 9JED, 9L42, 9LRE

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (1): 87–164

Glycosylation sites (2): 5, 9

Mutagenesis-validated functional residues (2):

Position	Phenotype
344	more than 30-fold reduced binding affinities of histamine.
348	more than 30-fold reduced binding affinities of histamine.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-390650	Histamine receptors
R-HSA-418594	G alpha (i) signalling events

MSigDB gene sets: 125 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELL_CELL_SIGNALING, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_SYNAPTIC_SIGNALING, GOBP_RESPONSE_TO_ACETYLCHOLINE, MYB_Q3, RYTTCCTG_ETS2_B, GOBP_ADENYLATE_CYCLASE_INHIBITING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (9): inflammatory response (GO:0006954), G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger (GO:0007187), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway (GO:0007197), positive regulation of cytosolic calcium ion concentration (GO:0007204), chemical synaptic transmission (GO:0007268), regulation of MAPK cascade (GO:0043408), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (3): histamine receptor activity (GO:0004969), neurotransmitter receptor activity (GO:0030594), G protein-coupled receptor activity (GO:0004930)

GO Cellular Component (4): plasma membrane (GO:0005886), dendrite (GO:0030425), synapse (GO:0045202), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Amine ligand-binding receptors	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
defense response	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1
G protein-coupled acetylcholine receptor signaling pathway	1
regulation of biological quality	1
anterograde trans-synaptic signaling	1
MAPK cascade	1
regulation of intracellular signal transduction	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
G protein-coupled amine receptor activity	1
histamine binding	1
signaling receptor activity	1
transmembrane signaling receptor activity	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1
cell junction	1
cellular anatomical structure	1

Protein interactions and networks

STRING

498 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HRH4	HDC	P19113	729
HRH4	TPM3	P06753	702
HRH4	TRPV1	Q8NER1	624
HRH4	HRH1	P35367	579
HRH4	IL31	Q6EBC2	570
HRH4	HRH3	Q9Y5N1	537
HRH4	SCGB1A1	P11684	490
HRH4	SSR3	Q9UNL2	475
HRH4	GATA1	P15976	470
HRH4	CD1A	P06126	465
HRH4	CCL16	O15467	460
HRH4	KITLG	P21583	457
HRH4	CEBPB	P17676	438
HRH4	OST4	P0C6T2	423
HRH4	GNA14	O95837	412

IntAct

8 interactions, top by confidence:

A	B	Type	Score
RAMP1	HRH4	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	HRH4	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	HRH4	psi-mi:“MI:0915”(physical association)	0.400
HRH4	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
HRH4	RAMP1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (1): TKT (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: O02300, O15973, O17239, O46635, O54798, O62169, O62729, O70342, O88319, O97967, O97969, P08909, P14842, P18599, P20789, P28223, P30989, P30994, P35363, P35367, P35371, P41595, P50128, P50129, P61793, P61794, P70585, P90745, Q02152, Q03566, Q09502, Q15760, Q15761, Q18534, Q2V2K5, Q5R4Q6, Q5WA50, Q61121, Q63634, Q75Z89

Diamond homologs: O01668, O02464, O02465, O15973, O16005, O16017, O16018, O16019, O16020, O18312, O18315, O18481, O18485, O18486, O57422, O61303, O96107, P04950, P06002, P08099, P08255, P08483, P09241, P11483, P15409, P16177, P17646, P20309, P22269, P24603, P28678, P28679, P28680, P28681, P29404, P31356, P35356, P35360, P35361, P35362

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
HRH4	“up-regulates activity”	GNAI1	binding
HRH4	“up-regulates activity”	GNAI3	binding
histamine	“up-regulates activity”	HRH4	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

62 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

327 predictions. Top by Δscore:

Variant	Effect	Δscore
18:24468949:GCT:G	donor_gain	1.0000
18:24468952:G:GG	donor_gain	1.0000
18:24468782:GTGCA:G	acceptor_loss	0.9900
18:24468783:TGCA:T	acceptor_loss	0.9900
18:24468784:GCA:G	acceptor_loss	0.9900
18:24468785:CAG:C	acceptor_loss	0.9900
18:24468786:A:AC	acceptor_loss	0.9900
18:24468787:G:A	acceptor_loss	0.9900
18:24468787:GGT:G	acceptor_gain	0.9900
18:24468947:ATGCT:A	donor_gain	0.9900
18:24468948:TGCT:T	donor_gain	0.9900
18:24468949:GCTG:G	donor_gain	0.9900
18:24468950:CT:C	donor_gain	0.9900
18:24468950:CTG:C	donor_loss	0.9800
18:24468951:TG:T	donor_loss	0.9800
18:24468952:G:A	donor_loss	0.9800
18:24468953:T:TA	donor_loss	0.9800
18:24468954:AAG:A	donor_loss	0.9800
18:24468955:A:AA	donor_loss	0.9800
18:24468956:G:C	donor_loss	0.9800
18:24468787:GGTGT:G	acceptor_gain	0.9700
18:24468883:T:G	donor_gain	0.9600
18:24468843:A:T	donor_gain	0.9400
18:24476506:TAGTA:T	acceptor_gain	0.9400
18:24468786:A:AG	acceptor_gain	0.9300
18:24468787:G:GG	acceptor_gain	0.9300
18:24468847:G:GT	donor_gain	0.9200
18:24476744:TAGG:T	acceptor_gain	0.9100
18:24476743:CTAGG:C	acceptor_gain	0.8900
18:24461043:GTT:G	acceptor_gain	0.8800

AlphaMissense

2530 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:24468919:A:C	S109R	0.991
18:24468921:C:A	S109R	0.991
18:24468921:C:G	S109R	0.991
18:24460896:C:A	N56K	0.989
18:24460896:C:G	N56K	0.989
18:24460911:C:A	D61E	0.988
18:24460911:C:G	D61E	0.988
18:24476807:T:A	W140R	0.988
18:24476807:T:C	W140R	0.988
18:24477323:T:C	F312L	0.986
18:24477325:T:A	F312L	0.986
18:24477325:T:G	F312L	0.986
18:24460846:T:C	F40L	0.984
18:24460848:T:A	F40L	0.984
18:24460848:T:G	F40L	0.984
18:24460910:A:C	D61A	0.983
18:24460910:A:T	D61V	0.982
18:24460921:G:C	G65R	0.982
18:24468929:G:C	R112P	0.982
18:24460827:T:A	N33K	0.981
18:24460827:T:G	N33K	0.981
18:24460909:G:C	D61H	0.980
18:24460910:A:G	D61G	0.980
18:24476936:T:C	F183L	0.980
18:24476938:C:A	F183L	0.980
18:24476938:C:G	F183L	0.980
18:24477335:T:A	W316R	0.978
18:24477335:T:C	W316R	0.978
18:24468788:G:A	G65D	0.977
18:24477482:T:C	F365L	0.977

dbSNP variants (sampled 300 via entrez): RS1000107188 (18:24480185 A>G), RS1000473676 (18:24474477 C>T), RS1000519267 (18:24478234 G>T), RS1000562455 (18:24479752 C>T), RS1000617070 (18:24469845 G>T), RS1000704422 (18:24475638 GAACA>G,GAACAAACA), RS1000872654 (18:24461357 A>G), RS1001577105 (18:24462589 G>A,C,T), RS1001695235 (18:24462556 T>C), RS1001729916 (18:24479460 T>G), RS1001912449 (18:24464307 G>A), RS1001966911 (18:24469473 G>T), RS1002018097 (18:24476487 C>T), RS1002224090 (18:24461782 A>G,T), RS1002235026 (18:24460490 T>C)

Disease associations

OMIM: gene MIM:606792 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001692_10	Response to taxane treatment (docetaxel)	8.000000e-06
GCST007576_65	Chronotype	6.000000e-13
GCST010423_4	Diastolic blood pressure x educational attainment (graduated college) interaction (2df)	5.000000e-08
GCST010988_73	Adult body size	2.000000e-09
GCST011974_4	Lung cancer	5.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004784	self reported educational attainment
EFO:0006336	diastolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111378 (SELECTIVITY GROUP), CHEMBL3759 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

18 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 438,057 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1172	DESLORATADINE	4	19,720
CHEMBL1423	PIMOZIDE	4	17,310
CHEMBL1533310	HISTAMINE DIHYDROCHLORIDE	4	8,186
CHEMBL296419	ASTEMIZOLE	4	21,577
CHEMBL301265	PRAMIPEXOLE	4	24,026
CHEMBL42	CLOZAPINE	4	37,581
CHEMBL534	KETOTIFEN	4	21,815
CHEMBL657	DIPHENHYDRAMINE	4	99,674
CHEMBL831	LOXAPINE	4	13,469
CHEMBL90	HISTAMINE	4	169,677
CHEMBL1197564	NORKETOTIFEN	2	131
CHEMBL12608	IMPROMIDINE	2	1,052
CHEMBL1767164	GSK-1004723	2	76
CHEMBL1915540	ADRIFORANT	2	241
CHEMBL3236549	JNJ-39758979	2	82
CHEMBL3301609	TOREFORANT	2	187
CHEMBL340801	PERLAPINE	2	3,226
CHEMBL5095103	IZUFORANT	2	27

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4483927	Efficacy	3	risperidone	Schizophrenia

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4483927	HRH4	3	1.25	1	risperidone
rs11662595	HRH4		0.00	0
rs11665084	HRH4		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Histamine receptors

Most potent curated ligand interactions (42 total), top 25:

Ligand	Action	Affinity	Parameter
imetit	Full agonist	8.9	pKi
[3H]histamine	Full agonist	8.4	pKd
[3H]JNJ 7777120	Antagonist	8.4	pKd
adriforant	Antagonist	8.31	pKi
clobenpropit	Partial agonist	8.3	pKi
JNJ 7777120	Antagonist	8.3	pKi
INCB-38579	Antagonist	8.3	pKi
histamine	Full agonist	8.3	pKi
4-methylhistamine	Full agonist	8.2	pKi
CCL16	Full agonist	8.1	pIC50
immepip	Full agonist	8.0	pKi
ST-1006	Agonist	7.9	pKi
JNJ-39758979	Antagonist	7.9	pKi
impromidine	Partial agonist	7.9	pKi
N-[3H]methylhistamine	Full agonist	7.8	pKd
[125I]CCL16 (human)	Full agonist	7.8	pKd
iodophenpropit	Antagonist	7.7	pKi
N-methylhistamine	Full agonist	7.6	pKi
thioperamide	Antagonist	7.6	pKi
H4 antagonist 48	Antagonist	7.57	pIC50
[3H]pyrilamine	Antagonist	7.5	pKd
VUF 8430	Full agonist	7.5	pKi
burimamide	Antagonist	7.4	pKi
[3H](R)-α-methylhistamine	Full agonist	7.2	pKd
N-α-methylhistamine	Full agonist	7.2	pKi

Binding affinities (BindingDB)

254 measured of 396 human assays (415 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
NSC_104911	KI	0.1 nM
3,3-diethyl-1-[(4R,7R)-6-methyl-6,11-diazatetracyclo[7.6.1.0^{2,7}.0^{12,16}]hexadeca-1(15),2,9,12(16),13-pentaen-4-yl]urea	KI	0.15 nM
2-(3H-imidazol-4-yl)ethylsulfanylmethanimidamide	KI	0.3 nM
4-(1H-imidazol-4-ylmethyl)piperidine	KI	0.4 nM
N(alpha)-Methylhistamine	KI	0.5 nM
4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine	KI	0.5 nM	US-9732087: Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
5-{3-[(4-iodophenyl)methoxy]propyl}-1H-imidazole	KI	0.63 nM
4-(1H-imidazol-5-ylmethyl)pyridine	KI	0.794 nM
2-[3-(1H-imidazol-4-ylmethyl)phenyl]-4,4,6-trimethyl-5,6-dihydro-4H-1,3-oxazine	KI	1 nM
2-{2-chloro-4-[3-(4-methyl-1,4-diazepan-1-yl)propoxy]phenyl}-4,6-dimethyl-1H-1,3-benzodiazole	KI	1 nM
Vistaril	KI	1 nM
4-(1H-imidazol-5-ylmethyl)-1-methylpiperidine	KI	1 nM
4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine	KI	1 nM	US-9732087: Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
N-(2-bicyclo[2.2.1]heptanyl)-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine	KI	1 nM	US-9732087: Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
N-(2-bicyclo[2.2.1]heptanyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine	KI	1 nM	US-9732087: Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
CHEMBL3236579	KI	1.7 nM
4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine	KI	1.7 nM	US-9732087: Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
1-(8-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine	KI	1.8 nM
N-butyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine	KI	2 nM	US-9732087: Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
VUF8328	KI	3 nM
4-N-(4-bromo-2-propan-2-yloxyphenyl)-4-N-propan-2-ylpyrimidine-2,4-diamine	KI	3 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
(S)-mianserin	KI	3 nM
4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine	KI	3.08 nM	US-9732087: Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
6-[(3R)-3-(methylamino)pyrrolidin-1-yl]-3,5-diazatricyclo[9.4.0.0^{2,7}]pentadeca-1(15),2(7),3,5,11,13-hexaen-4-amine	KI	3.5 nM
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine dihydrochloride	KI	3.5 nM	US-9732087: Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
4-{[3-(3,3-dimethylbut-1-yn-1-yl)phenyl]methyl}-1H-imidazole	KI	4 nM
4-(1H-imidazol-5-yl)butan-1-amine	KI	4 nM
4-N-propan-2-yl-4-N-[2-propyl-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine	KI	4 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
A-943931	KI	4.7 nM
N-Cyclohexyl-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine	KI	4.8 nM	US-9732087: Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
5-(1H-imidazol-5-yl)pentan-1-amine	KI	5 nM
4-(4-methylpiperazin-1-yl)-6-phenylpyrimidin-2-amine	KI	5 nM
14-fluoro-6-(piperazin-1-yl)-3,5-diazatricyclo[9.4.0.0^{2,7}]pentadeca-1(15),2(7),3,5,11,13-hexaen-4-amine	KI	5.1 nM
5-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridazin-3-amine	KI	5.9 nM	US-9732087: Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
4-N-(2-ethoxy-4-fluorophenyl)-4-N-propan-2-ylpyrimidine-2,4-diamine	KI	6 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
4-N-[2-methyl-4-(pentafluoro-lambda6-sulfanyl)phenyl]-4-N-propan-2-ylpyrimidine-2,4-diamine	KI	7 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
4-N-[2-methyl-4-(pentafluoro-lambda6-sulfanyl)phenyl]-4-N-(1,3-thiazol-4-ylmethyl)pyrimidine-2,4-diamine	KI	7 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
4-N-propan-2-yl-4-N-[2-[(E)-prop-1-enyl]-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine	KI	7 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
4-N-(4-fluoro-2-propylphenyl)-4-N-propan-2-ylpyrimidine-2,4-diamine	KI	7 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
VUF-10497	KI	7.6 nM	US-12492199: Pyridopyrimidines as histamine H4-receptor inhibitors
1-[4-(1H-imidazol-4-yl)butyl]-3-propan-2-ylthiourea	KI	8 nM
4-N-[2-ethyl-4-(pentafluoro-lambda6-sulfanyl)phenyl]-4-N-(1,3-oxazol-4-ylmethyl)pyrimidine-2,4-diamine	KI	8 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
4-N-[2-cyclobutyl-4-(trifluoromethylsulfonyl)phenyl]-4-N-ethylpyrimidine-2,4-diamine	KI	8 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
4-N-[4-bromo-2-(trifluoromethoxy)phenyl]-4-N-propan-2-ylpyrimidine-2,4-diamine	KI	8 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
2-{2-chloro-4-[3-(4-methyl-1,4-diazepan-1-yl)propoxy]phenyl}-4,5-dimethyl-1H-1,3-benzodiazole	KI	9 nM
4-N-[2-cyclobutyl-4-(trifluoromethoxy)phenyl]-4-N-(1,3-oxazol-4-ylmethyl)pyrimidine-2,4-diamine	KI	9 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
4-N-[2-methyl-4-(pentafluoro-lambda6-sulfanyl)phenyl]-4-N-(1,3-oxazol-4-ylmethyl)pyrimidine-2,4-diamine	KI	9 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
4-N-[2-ethyl-4-(pentafluoro-lambda6-sulfanyl)phenyl]-4-N-(1H-pyrazol-5-ylmethyl)pyrimidine-2,4-diamine	KI	9 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
4-N-[(5-methyl-1,3-oxazol-4-yl)methyl]-4-N-[2-methyl-4-(pentafluoro-lambda6-sulfanyl)phenyl]pyrimidine-2,4-diamine	KI	9 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators
4-N-[2-ethyl-4-(trifluoromethyl)phenyl]-4-N-(1,3-oxazol-4-ylmethyl)pyrimidine-2,4-diamine	KI	9 nM	US-10172856: 2,4-diaminopyrimidine derivatives as histamine H4 modulators

ChEMBL bioactivities

2312 potent at pChembl≥5 of 2457 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.47	Ki	0.034	nM	CHEMBL1915536
10.40	Ki	0.04	nM	CHEMBL1770975
10.10	Kd	0.07943	nM	CHEMBL3393547
10.00	Kd	0.1	nM	CHEMBL3236561
10.00	Ki	0.1	nM	CHEMBL1914541
9.91	EC50	0.123	nM	CHEMBL4454158
9.90	Kd	0.1259	nM	CHEMBL3236552
9.70	Ki	0.2	nM	CHEMBL1770971
9.68	Ki	0.21	nM	CHEMBL1083162
9.60	Kd	0.2512	nM	CHEMBL3236554
9.52	Ki	0.3	nM	CHEMBL1770968
9.52	Ki	0.3	nM	CHEMBL1914462
9.50	Kd	0.3162	nM	CHEMBL3236553
9.40	Kd	0.3981	nM	CHEMBL3236575
9.40	Kd	0.3981	nM	CHEMBL1770980
9.40	Ki	0.4	nM	CHEMBL1091874
9.30	Ki	0.5	nM	CHEMBL5949302
9.30	Kd	0.5012	nM	CHEMBL1770979
9.25	EC50	0.56	nM	CHEMBL1083162
9.22	EC50	0.6026	nM	CHEMBL4443126
9.20	Kd	0.631	nM	CHEMBL3236556
9.20	Kd	0.631	nM	CHEMBL3393526
9.19	IC50	0.65	nM	ADRIFORANT
9.15	Ki	0.7	nM	CHEMBL1914781
9.10	Ki	0.8	nM	CHEMBL3393547
9.10	Ki	0.8	nM	CHEMBL1914755
9.05	Ki	0.9	nM	CHEMBL1770973
9.05	Ki	0.9	nM	CHEMBL1914750
9.04	Ki	0.92	nM	CHEMBL3236556
9.00	Ki	1	nM	CHEMBL3236553
9.00	Ki	1	nM	CHEMBL3393534
9.00	Kd	1	nM	CHEMBL3393532
9.00	Kd	1	nM	CHEMBL3393535
9.00	Ki	1	nM	CHEMBL3819260
9.00	Ki	1	nM	CHEMBL373579
9.00	Ki	1	nM	HISTAMINE
9.00	Ki	1	nM	CHEMBL5912704
9.00	Ki	1	nM	CHEMBL3393556
9.00	IC50	1	nM	CHEMBL1091874
9.00	EC50	1	nM	CHEMBL1688946
9.00	Ki	1	nM	CHEMBL1771001
9.00	Ki	1	nM	CHEMBL1770992
9.00	Ki	1	nM	CHEMBL1914760
9.00	Ki	1	nM	CHEMBL1914783
9.00	Ki	1	nM	CLOBENPROPIT
8.96	Ki	1.1	nM	CHEMBL3236554
8.96	Ki	1.1	nM	CHEMBL1098230
8.96	Ki	1.1	nM	CHEMBL1914540
8.96	Ki	1.1	nM	CHEMBL1914542
8.95	EC50	1.122	nM	CHEMBL595180

PubChem BioAssay actives

2098 with measured affinity, of 3834 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-N-(2,2-dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine	627670: Antagonist activity at full length human H4R expressed in HEK293 cells assessed as reversal of forskolin-induced cAMP production by CRE-beta-lactamase reporter gene assay	ki	<0.0001	uM
6-N-(2,2-dimethylpropyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridine-2,6-diamine	594143: Displacement of [3H]histamine from human histamine H4 receptor	ki	<0.0001	uM
N-(2-bicyclo[2.2.1]heptanyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine	1190704: Antagonist activity at human recombinant histamine H4 receptor expressed in SK-N-MC cells assessed as inhibition of forskolin-stimulated cAMP-mediated reporter gene activity	kd	<0.0001	uM
N-(2,2-dimethylpropyl)-4-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)pyrimidin-2-amine;bis(2,2,2-trifluoroacetic acid)	1540397: Agonist activity at human H4R expressed in HEK293-SF-hH4R-His6-CRE-Luc cells incubated for 5 hrs by luciferase reporter gene assay	ec50	0.0001	uM
8-chloro-4-(4-methylpiperazin-1-yl)-[1]benzofuro[3,2-d]pyrimidin-2-amine	628647: Displacement of [3H]histamine from recombinant human histamine H4 receptor	ki	0.0001	uM
4-cyclopentyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine	1127888: Antagonist activity at human histamine H4 receptor expressed in SK-N-MC cells assessed as reduction of histamine-induced inhibition of cAMP-mediated beta-galactosidase reporter gene activity treated 10 mins prior to histamine challenge by microplate reader analysis	kd	0.0001	uM
4-[(4aR,7aR)-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-6-cyclopentylpyrimidin-2-amine	1127888: Antagonist activity at human histamine H4 receptor expressed in SK-N-MC cells assessed as reduction of histamine-induced inhibition of cAMP-mediated beta-galactosidase reporter gene activity treated 10 mins prior to histamine challenge by microplate reader analysis	kd	0.0001	uM
N-(2-bicyclo[2.2.1]heptanyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine	1190704: Antagonist activity at human recombinant histamine H4 receptor expressed in SK-N-MC cells assessed as inhibition of forskolin-stimulated cAMP-mediated reporter gene activity	kd	0.0001	uM
4-[(3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[2,3-c]pyrrol-5-yl]-6-cyclopentylpyrimidin-2-amine	1127888: Antagonist activity at human histamine H4 receptor expressed in SK-N-MC cells assessed as reduction of histamine-induced inhibition of cAMP-mediated beta-galactosidase reporter gene activity treated 10 mins prior to histamine challenge by microplate reader analysis	kd	0.0001	uM
4-cyclohexyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine	1127888: Antagonist activity at human histamine H4 receptor expressed in SK-N-MC cells assessed as reduction of histamine-induced inhibition of cAMP-mediated beta-galactosidase reporter gene activity treated 10 mins prior to histamine challenge by microplate reader analysis	kd	0.0001	uM
4-(1-adamantyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine	1127888: Antagonist activity at human histamine H4 receptor expressed in SK-N-MC cells assessed as reduction of histamine-induced inhibition of cAMP-mediated beta-galactosidase reporter gene activity treated 10 mins prior to histamine challenge by microplate reader analysis	kd	0.0001	uM
3-[4-(5-fluoro-4-methyl-1H-benzimidazol-2-yl)-3-methylphenoxy]-N-[2-(1H-imidazol-5-yl)ethyl]propan-1-amine	483141: Displacement of [3H]histamine from human recombinant histamine H4 receptor	ki	0.0002	uM
4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6-N-(2-methylpropyl)pyridine-2,6-diamine	594143: Displacement of [3H]histamine from human histamine H4 receptor	ki	0.0002	uM
4-cyclopentyl-6-piperazin-1-ylpyrimidin-2-amine	1127888: Antagonist activity at human histamine H4 receptor expressed in SK-N-MC cells assessed as reduction of histamine-induced inhibition of cAMP-mediated beta-galactosidase reporter gene activity treated 10 mins prior to histamine challenge by microplate reader analysis	kd	0.0003	uM
8-chloro-4-(4-methylpiperazin-1-yl)-[1]benzothiolo[3,2-d]pyrimidin-2-amine	628647: Displacement of [3H]histamine from recombinant human histamine H4 receptor	ki	0.0003	uM
4-cyclopentyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine	1127888: Antagonist activity at human histamine H4 receptor expressed in SK-N-MC cells assessed as reduction of histamine-induced inhibition of cAMP-mediated beta-galactosidase reporter gene activity treated 10 mins prior to histamine challenge by microplate reader analysis	kd	0.0003	uM
6-N-(2,2-dimethylpropyl)-4-(4-methylpiperazin-1-yl)pyridine-2,6-diamine	594143: Displacement of [3H]histamine from human histamine H4 receptor	ki	0.0003	uM
8-chloro-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-[1]benzofuro[3,2-d]pyrimidin-2-amine	628647: Displacement of [3H]histamine from recombinant human histamine H4 receptor	ki	0.0004	uM
4-cyclobutyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine	1127888: Antagonist activity at human histamine H4 receptor expressed in SK-N-MC cells assessed as reduction of histamine-induced inhibition of cAMP-mediated beta-galactosidase reporter gene activity treated 10 mins prior to histamine challenge by microplate reader analysis	kd	0.0004	uM
4-N-cyclopentyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine	594145: Antagonist activity at human histamine H4 receptor expressed in human SK-N-MC cells assessed as inhibition of forskolin-stimulated cAMP accumulation after 6 hrs	kd	0.0004	uM
6-[(3R)-3-(methylamino)pyrrolidin-1-yl]-4-N-(2-methylpropyl)pyrimidine-2,4-diamine	594145: Antagonist activity at human histamine H4 receptor expressed in human SK-N-MC cells assessed as inhibition of forskolin-stimulated cAMP accumulation after 6 hrs	kd	0.0005	uM
N-(2,2-dimethylpropyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;bis(2,2,2-trifluoroacetic acid)	1540397: Agonist activity at human H4R expressed in HEK293-SF-hH4R-His6-CRE-Luc cells incubated for 5 hrs by luciferase reporter gene assay	ec50	0.0006	uM
4-N-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine	627793: Antagonist activity at H4R in human eosinophils assessed as inhibition of histamine-induced shape change by GAFS assay	ic50	0.0006	uM
4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine	1190704: Antagonist activity at human recombinant histamine H4 receptor expressed in SK-N-MC cells assessed as inhibition of forskolin-stimulated cAMP-mediated reporter gene activity	kd	0.0006	uM
4-[(3R)-3-aminopyrrolidin-1-yl]-6-cyclopentylpyrimidin-2-amine	1127888: Antagonist activity at human histamine H4 receptor expressed in SK-N-MC cells assessed as reduction of histamine-induced inhibition of cAMP-mediated beta-galactosidase reporter gene activity treated 10 mins prior to histamine challenge by microplate reader analysis	kd	0.0006	uM
8-bromo-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-[1]benzofuro[3,2-d]pyrimidin-2-amine	628647: Displacement of [3H]histamine from recombinant human histamine H4 receptor	ki	0.0007	uM
4-(4-methylpiperazin-1-yl)-8-(trifluoromethyl)-[1]benzofuro[3,2-d]pyrimidin-2-amine	628647: Displacement of [3H]histamine from recombinant human histamine H4 receptor	ki	0.0008	uM
8-chloro-4-[3-(methylamino)pyrrolidin-1-yl]-[1]benzofuro[3,2-d]pyrimidin-2-amine	628647: Displacement of [3H]histamine from recombinant human histamine H4 receptor	ki	0.0009	uM
6-N-cyclopentyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridine-2,6-diamine	594143: Displacement of [3H]histamine from human histamine H4 receptor	ki	0.0009	uM
2-[2-chloro-4-[3-(4-methyl-1,4-diazepan-1-yl)propoxy]phenyl]-4,6-dimethyl-1H-benzimidazole	1798211: Radioligand Binding Assay from Article 10.1016/j.bmcl.2006.08.117: “Identification of 2-arylbenzimidazoles as potent human histamine H4 receptor ligands.”	ki	0.0010	uM
4-N-cyclopentyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine	594143: Displacement of [3H]histamine from human histamine H4 receptor	ki	0.0010	uM
8-bromo-4-(4-methylpiperazin-1-yl)-[1]benzothiolo[3,2-d]pyrimidin-2-amine	628647: Displacement of [3H]histamine from recombinant human histamine H4 receptor	ki	0.0010	uM
3-(1H-imidazol-5-yl)propyl N’-[(4-chlorophenyl)methyl]carbamimidothioate	632458: Displacement of [3H]histamine from human H4 receptor Q7.42L mutant expressed in HEK293 cells after 1 to 1.5 hrs by scintillation counting	ki	0.0010	uM
4-(cyclohexylmethyl)-1-[3-(1H-imidazol-5-yl)propyl]triazole	586696: Agonist activity at human histamine H4 receptor expressed in HEK293 cells assessed by forskolin induced cAMP response element activation by luciferase reporter gene assay	ec50	0.0010	uM
6-[(3R)-3-(methylamino)pyrrolidin-1-yl]-2-N-(2-methylpropyl)pyrimidine-2,4-diamine	594143: Displacement of [3H]histamine from human histamine H4 receptor	ki	0.0010	uM
4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-8-(trifluoromethyl)-[1]benzofuro[3,2-d]pyrimidin-2-amine	628647: Displacement of [3H]histamine from recombinant human histamine H4 receptor	ki	0.0010	uM
N-(2-bicyclo[2.2.1]heptanyl)-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine	1190704: Antagonist activity at human recombinant histamine H4 receptor expressed in SK-N-MC cells assessed as inhibition of forskolin-stimulated cAMP-mediated reporter gene activity	kd	0.0010	uM
N-cyclopentyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine	1190704: Antagonist activity at human recombinant histamine H4 receptor expressed in SK-N-MC cells assessed as inhibition of forskolin-stimulated cAMP-mediated reporter gene activity	kd	0.0010	uM
Histamine	1693528: Displacement of [3H]-Histamine from human histamine 4 receptor transfected in HEK293T cells incubated for 16 hrs by liquid scintillation counter analysis	ki	0.0010	uM
8-chloro-4-piperazin-1-yl-[1]benzofuro[3,2-d]pyrimidin-2-amine	628647: Displacement of [3H]histamine from recombinant human histamine H4 receptor	ki	0.0011	uM
8-chloro-4-(1,4-diazepan-1-yl)-[1]benzofuro[3,2-d]pyrimidin-2-amine	628647: Displacement of [3H]histamine from recombinant human histamine H4 receptor	ki	0.0011	uM
4-N-[(2,6-dichlorophenyl)methyl]-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine	452998: Agonist activity at human histamine H4 receptor expressed in Sf9 cells co-expressing Galphai2 and Gbeta1gamma2 assessed as stimulation of [35S]GTPgammaS binding	ec50	0.0011	uM
5-[2-(4-tert-butylphenyl)sulfanylethyl]-1H-imidazole	479114: Inhibition of human recombinant histamine H4 receptor expressed in CHO cells	ki	0.0011	uM
N-(2,2-dimethylpropyl)-4-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)pyrimidin-2-amine	1649747: Inhibition of UR-DEBa242 binding to human recombinant NLuc/GPCR-fused H4R expressed in HEK293T cells measured after 30 mins by furimazine substrate based BRET assay	ki	0.0012	uM
6-(4-methylpiperazin-1-yl)-4-N-(2-methylpropyl)pyrimidine-2,4-diamine	594145: Antagonist activity at human histamine H4 receptor expressed in human SK-N-MC cells assessed as inhibition of forskolin-stimulated cAMP accumulation after 6 hrs	kd	0.0013	uM
4-N-(3,3-dimethylbutyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine	627670: Antagonist activity at full length human H4R expressed in HEK293 cells assessed as reversal of forskolin-induced cAMP production by CRE-beta-lactamase reporter gene assay	ki	0.0015	uM
4-butyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine	1127886: Displacement of [3H]histamine from human recombinant histamine H4 receptor expressed in SK-N-MC cells after 45 mins by competition binding analysis	ki	0.0015	uM
4-[3-(methylamino)azetidin-1-yl]spiro[6,7-dihydro-5H-quinazoline-8,1’-cyclopentane]-2-amine	464136: Displacement of [3H]-histamine from human histamine H4 receptor expressed in HEK293 cells after 1 hr by liquid scintillation counting	ki	0.0015	uM
2-(1H-imidazol-5-yl)ethyl carbamimidothioate	597171: Displacement of [3H]histamine from human full-length histamine H4 receptor expressed in HEK293 cells after 60 mins	ki	0.0016	uM
3-(1H-imidazol-5-yl)propyl N’-[(3,4-dichlorophenyl)methyl]carbamimidothioate	586699: Agonistic activity at histamine H4 receptor	ki	0.0016	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
clobenpropit	decreases expression, increases expression, affects binding, decreases reaction, increases abundance (+2 more)	3
Histamine	increases abundance, increases phosphorylation, increases reaction, decreases expression, decreases reaction (+4 more)	3
alpha-methylhistamine	increases reaction, affects binding, increases activity, increases abundance, increases expression	2
1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine	increases abundance, increases activity, increases response to substance, affects binding, decreases reaction	2
Calcium	affects binding, decreases reaction, increases abundance, increases activity	2
Ozone	affects expression, increases abundance, decreases expression	2
Asian ginseng	affects cotreatment, decreases expression, decreases reaction	1
triphenyl phosphate	affects expression	1
4-methylhistamine	affects binding, decreases reaction, increases abundance, increases activity	1
S-(1,2-dichlorovinyl)cysteine	increases expression	1
N-methylhistamine	affects binding, increases activity, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
imetit	affects binding, increases activity, increases abundance	1
U 0126	decreases expression, decreases reaction, increases activity	1
Decitabine	decreases expression, decreases reaction	1
Air Pollutants	affects expression, increases abundance	1
Allergens	increases expression	1
Cadaverine	affects binding, increases activity	1
Diethylhexyl Phthalate	decreases expression, decreases reaction, affects cotreatment	1
Methotrexate	decreases expression	1
Smoke	decreases expression, decreases reaction	1
Tretinoin	decreases expression	1
Guanosine 5’-O-(3-Thiotriphosphate)	affects binding, increases reaction	1
Zinc Sulfate	decreases expression	1
Pertussis Toxin	decreases reaction, increases expression	1
Soot	decreases expression, increases abundance	1

ChEMBL screening assays

483 unique, capped per target: 348 binding, 133 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL700773	Binding	Selectivity expressed as the ratio of Ki for Histamine H4 receptor to that of Ki for Histamine H3 receptor	Identification of 4-(1H-imidazol-4(5)-ylmethyl)pyridine (immethridine) as a novel, potent, and highly selective histamine H(3) receptor agonist. — J Med Chem
CHEMBL845645	Functional	Maximum response compared to histamine against either H3 or H4 receptors	Identification of 4-(1H-imidazol-4(5)-ylmethyl)pyridine (immethridine) as a novel, potent, and highly selective histamine H(3) receptor agonist. — J Med Chem
CHEMBL4406632	ADMET	Displacement of [3H]-Histamine from recombinant human histamine H4 receptor expressed in HEKT cell membranes measured after 90 mins by microbeta scintillation counting method	Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist. — J Med Chem

Cellosaurus cell lines

2 cell lines: 1 spontaneously immortalized cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_H450	CHO-K1/H4/Galpha15	Spontaneously immortalized cell line	Female
CVCL_LA51	PathHunter U2OS HRH4 beta-arrestin	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.