HRH1

Summary

HRH1 (histamine receptor H1, HGNC:5182) is a protein-coding gene on chromosome 3p25.3, encoding Histamine H1 receptor (P35367). G-protein-coupled receptor for histamine, a biogenic amine that functions as an immune modulator and a neurotransmitter.

Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by histamine receptors H1, H2, H3 and H4. The protein encoded by this gene is an integral membrane protein and belongs to the G protein-coupled receptor superfamily. It mediates the contraction of smooth muscles, the increase in capillary permeability due to contraction of terminal venules, the release of catecholamine from adrenal medulla, and neurotransmission in the central nervous system. It has been associated with multiple processes, including memory and learning, circadian rhythm, and thermoregulation. It is also known to contribute to the pathophysiology of allergic diseases such as atopic dermatitis, asthma, anaphylaxis and allergic rhinitis. Multiple alternatively spliced variants, encoding the same protein, have been identified.

Source: NCBI Gene 3269 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 39 total
• Phenotypes (HPO): 1
• Druggable target: yes — 268 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001098212

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5182
Approved symbol	HRH1
Name	histamine receptor H1
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000196639
Ensembl biotype	protein_coding
OMIM	600167
Entrez	3269

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 15 protein_coding

ENST00000397056, ENST00000413416, ENST00000431010, ENST00000438284, ENST00000903200, ENST00000903201, ENST00000903202, ENST00000903203, ENST00000903204, ENST00000903205, ENST00000903206, ENST00000903207, ENST00000958939, ENST00000958940, ENST00000958941

RefSeq mRNA: 4 — MANE Select: NM_001098212 NM_000861, NM_001098211, NM_001098212, NM_001098213

CCDS: CCDS2604

Canonical transcript exons

ENST00000431010 — 2 exons

Exon	Start	End
ENSE00001527144	11259003	11263557
ENSE00001725401	11154493	11154554

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 87.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.2479 / max 62.5123, expressed in 1077 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35322	1.0080	597
35325	0.7459	376
35326	0.6128	216
35321	0.5021	249
35323	0.3072	190
202672	0.0721	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	87.86	gold quality
tendon of biceps brachii	UBERON:0008188	85.54	gold quality
descending thoracic aorta	UBERON:0002345	84.63	gold quality
calcaneal tendon	UBERON:0003701	83.98	gold quality
mucosa of urinary bladder	UBERON:0001259	83.90	gold quality
layer of synovial tissue	UBERON:0007616	83.26	gold quality
tendon	UBERON:0000043	81.99	gold quality
thoracic aorta	UBERON:0001515	81.06	gold quality
ascending aorta	UBERON:0001496	80.85	gold quality
synovial joint	UBERON:0002217	80.32	gold quality
stromal cell of endometrium	CL:0002255	80.17	gold quality
blood vessel layer	UBERON:0004797	79.43	gold quality
endothelial cell	CL:0000115	78.98	gold quality
aorta	UBERON:0000947	78.76	gold quality
dorsal root ganglion	UBERON:0000044	77.86	gold quality
pericardium	UBERON:0002407	77.48	gold quality
gall bladder	UBERON:0002110	77.05	gold quality
popliteal artery	UBERON:0002250	77.03	gold quality
right coronary artery	UBERON:0001625	76.99	gold quality
tibial artery	UBERON:0007610	76.99	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.02	gold quality
tongue squamous epithelium	UBERON:0006919	76.01	gold quality
gingival epithelium	UBERON:0001949	75.33	gold quality
vena cava	UBERON:0004087	75.15	gold quality
tibial nerve	UBERON:0001323	75.06	gold quality
mucosa of sigmoid colon	UBERON:0004993	74.81	gold quality
left coronary artery	UBERON:0001626	74.55	gold quality
coronary artery	UBERON:0001621	74.50	gold quality
rectum	UBERON:0001052	74.39	gold quality
sigmoid colon	UBERON:0001159	74.19	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.31
E-GEOD-124858	no	145.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

107 targeting HRH1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-3180-5P	99.82	69.12	2422

Literature-anchored findings (GeneRIF, showing 40)

• could be detected at the feto-maternal interface of human (PMID:11603849)
• expressed on monocyte-derived dendritic cells (PMID:11898002)
• genetic variant of this protein and body weight change during clozapine treatment in schizophrenia (PMID:12218662)
• markedly different potency for activation of multiple signaling pathways by H1- and H2-HRs (PMID:12680587)
• there are three mechanisms for h1 receptor down regulation: phosphorylation of thr-140 or ser-398 or five sites (PMID:12755404)
• No significant differences in H1R or H2R mRNA levels between seasonal allergic rhinitic and nonrhinitic subjects in-season, despite observed differences in H reactivity. (PMID:12757445)
• Thr140 and Ser398 mainly contributed to downregulation, and Thr142 or Ser396 had a slight inhibitory effect on Thr140- or Ser398-mediated process, respectively (PMID:15328002)
• rapid termination of H1HR signaling is mediated by both the kinase activity and RGS function of GRK2 (PMID:15542600)
• expression of the histamine (H) receptors 1 (H1) and 2 (H2) by germinal, interstitial, and peritubular cells in the testes of fertile and infertile patients (PMID:15820830)
• gene expression regulation of HRH1 gene by HRH1 (PMID:15928828)
• expression in chondrocytes of osteoarthritic cartilage (PMID:15928843)
• analysis of agonist binding to histamine H(1) receptor (PMID:16027157)
• characterization of important steps in the activation of the human histamine H1 receptor (PMID:16408006)
• These data suggest the use of alternative promoters directing human H1 receptor gene expression, both within and between cell types. (PMID:16484687)
• The H1R-PKC-ERK pathway may play crucial roles in eliciting cytokine production from bronchial epithelial cells stimulated by histamine, leading to airway inflammation (PMID:16491014)
• results exclude the participation of histamine receptors other than the H1 subtype in the control of human intestinal motility by oxogenous histamine (PMID:16547808)
• histamine stimulates integrin alpha-V beta-3 expression in cultured trophoblast cells; the H1 receptor is implicated (PMID:16705383)
• Ascorbate enhancement of seven-transmembrane-spanning membrane receptor activity occurs in both adrenergic and histaminergic receptors. These receptors may play a significant role in maintaining extracellular ascorbate in a reduced state. (PMID:16760260)
• These data suggest postexercise skeletal muscle hyperemia exists in endurance trained men and women. (PMID:16888049)
• Histamine stimulates IL-6 release from SW982 cells by binding to the H1 receptor and this is coupled to the PI/PKC signal transduction pathway. (PMID:17122961)
• The data suggest a global functional analogy between H1 receptor activation and the meta I/meta II charge/discharge equilibrium in rhodopsin. (PMID:17243823)
• Cytokine-induced endothelial intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expressionwas inhibited by tecastemazole in a manner independent of H1 receptor antagonism. (PMID:17517105)
• roles of dermatopontin and histamine receptor H1 genes as downstream targets for the VDR were confirmed by gel electromotility shift and chromatin immunoprecipitation assays that showed the presence of VDR complex binding sequences (PMID:17547532)
• Histamine excites human enteric neurones and this effect involves histamine H1-4 receptors. (PMID:17627982)
• M3R was involved in the up-regulation of H1R by activating H1R gene transcription through a PKC-dependent process. (PMID:17637176)
• a dramatic alteration in the distribution of histamine receptors in colon cancer (PMID:18258331)
• Results describe the molecular interactions between histamine and the human H1 receptor that influence phospholipase C and cyclic AMP signaling. (PMID:18345497)
• These results indicate that the polymorphisms analyzed are not a major risk factor for Parkinson disease, although the HRH1Leu449Ser amino acid substitution might be related to PD (PMID:18366640)
• Internalization-mediated changes in the binding properties of H1-receptor antagonists were well correlated with their sedative and non-sedative behaviors. (PMID:18446005)
• results indicate that the beta2AR is involved in the down-regulation of human H1R by inhibiting H1R gene transcription through a PKA-dependent process (PMID:18498711)
• Histamine stimulates phospholipase C-signaling in myometrial smooth muscle cells through H(1) histamine receptors and that GRK2 recruitment is a key mechanism in the regulation of H(1) histamine receptor signaling in human uterine smooth muscle. (PMID:18511496)
• Histamine upregulates keratinocyte MMP-9 production via the histamine H1 receptor (PMID:18548114)
• Histamine-induced Egr-1 expression is dependent on the activation of the H1 receptor, and rapidly and transiently activates PKCdelta, ERK1/2, p38 kinase, and JNK prior to Egr-1 induction. (PMID:18682391)
• anorexia nervosa patients may have higher expression of H1R in the limbic brain, particularly in the amygdala (PMID:18814859)
• Results compare the correlation between H1-receptor expression and SLPI levels within cultured amniotic epithelial cells derived from chorioamnionitis-complicated and normal pregnancies. (PMID:19271144)
• Human salivary gland cells express histamine H1 receptors and histamine-synthesizing enzymes, revealing the cellular mechanism of antihistamine-induced xerostomia. (PMID:19443731)
• Functional coupling of the H1R to Gq-PLC leads to the activation of RhoA and Rac small GTPases and suggest distinct roles for Rho GTPases in the control of cell proliferation by histamine. (PMID:19913013)
• Results demonstrate that LPS, through TLR4 activation, up-regulates the expression and function of H1R and amplifies histamine-induced inflammatory responses in HCAEC. (PMID:21255012)
• Measurement of H1R occupancy is a sensitive and absolute method to characterize the non-sedating property of drugs with H1 antagonistic activity. (PMID:21433074)
• H1 and PAR2 receptors enhance delivery of immune-competent cells and molecules by interrupting E-cadherin adhesion in lung epithelial cells. (PMID:21686228)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hrh1	ENSMUSG00000053004
rattus_norvegicus	Hrh1	ENSRNOG00000007420
drosophila_melanogaster	mAChR-C	FBGN0029909

Paralogs (25): DRD4 (ENSG00000069696), HRH3 (ENSG00000101180), HRH2 (ENSG00000113749), CHRM3 (ENSG00000133019), HRH4 (ENSG00000134489), 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), GPR52 (ENSG00000203737), TAAR9 (ENSG00000237110)

Protein

Protein identifiers

Histamine H1 receptor — P35367 (reviewed: P35367)

All UniProt accessions (2): C9J2E6, P35367

UniProt curated annotations — full annotation on UniProt →

Function. G-protein-coupled receptor for histamine, a biogenic amine that functions as an immune modulator and a neurotransmitter. Through the H1 receptor, histamine mediates the contraction of smooth muscles and increases capillary permeability due to contraction of terminal venules. Also mediates neurotransmission in the central nervous system and thereby regulates circadian rhythms, emotional and locomotor activities as well as cognitive functions.

Subcellular location. Cell membrane.

Post-translational modifications. Phosphorylation at sites in the second and third cytoplasmic loops independently contribute to agonist-induced receptor down-regulation.

Domain organisation. Histamine activates the receptor by forming hydrogen bonds with transmembrane domains 3 and 6, squashing the ligand-binding pocket on the extracellular side and opening the cavity for G-protein engagement on the intracellular side.

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

RefSeq proteins (4): NP_000852, NP_001091681, NP_001091682, NP_001091683 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000921	Histamine_H1_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (83 total): mutagenesis site 20, helix 16, modified residue 9, topological domain 8, transmembrane region 7, region of interest 4, binding site 4, strand 4, sequence variant 3, compositionally biased region 2, glycosylation site 2, disulfide bond 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
8YN2	ELECTRON MICROSCOPY	2.66
9LRB	ELECTRON MICROSCOPY	2.77
8X5Y	ELECTRON MICROSCOPY	3
3RZE	X-RAY DIFFRACTION	3.1
8X63	ELECTRON MICROSCOPY	3.2
9LRD	ELECTRON MICROSCOPY	3.23
7DFL	ELECTRON MICROSCOPY	3.3
8X64	ELECTRON MICROSCOPY	3.4
8X5X	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35367-F1	70.95	0.40

Antibody-complex structures (SAbDab): 4 — 7DFL, 8YN2, 9LRB, 9LRD

Functional residue map

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

Ligand- & substrate-binding residues (4): 107; 112; 198; 431

Post-translational modifications (9): 140, 142, 230, 279, 344, 347, 380, 396, 398

Disulfide bonds (2): 100–180, 441–444

Glycosylation sites (2): 5, 18

Mutagenesis-validated functional residues (20):

Position	Phenotype
56	no effect on activation by histamine.
57	no effect on activation by histamine.
59	no effect on activation by histamine.
107	loss of activation by histamine.
108	no effect on activation by histamine.
108	decreased activation by histamine.
111	no effect on activation by histamine.
112	decreased activation by histamine.
135	no effect on activation by histamine.
137	no effect on activation by histamine.
158	loss of activation by histamine.
198	loss of activation by histamine.
428	loss of activation by histamine.
431	loss of activation by histamine.
431	increased histamine receptor activity. constitutively active.
432	no effect on activation by histamine.
435	decreased activation by histamine.
454	no effect on activation by histamine.
458	decreased activation by histamine.
458	no effect on activation by histamine.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-390650	Histamine receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 207 (showing top): GOBP_MEMORY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_ASSOCIATIVE_LEARNING, GEORGES_CELL_CYCLE_MIR192_TARGETS, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_POSITIVE_REGULATION_OF_VASOCONSTRICTION, GOBP_REGULATION_OF_SYNAPTIC_PLASTICITY, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, WATANABE_RECTAL_CANCER_RADIOTHERAPY_RESPONSIVE_UP

GO Biological Process (13): inflammatory response (GO:0006954), G protein-coupled receptor signaling pathway (GO:0007186), G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger (GO:0007187), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), chemical synaptic transmission (GO:0007268), memory (GO:0007613), visual learning (GO:0008542), regulation of vascular permeability (GO:0043114), positive regulation of vasoconstriction (GO:0045907), regulation of synaptic plasticity (GO:0048167), cellular response to histamine (GO:0071420), signal transduction (GO:0007165), phospholipase C-activating serotonin receptor signaling pathway (GO:0007208)

GO Molecular Function (2): histamine receptor activity (GO:0004969), G protein-coupled receptor activity (GO:0004930)

GO Cellular Component (5): cytosol (GO:0005829), 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	3
regulation of biological quality	2
cellular anatomical structure	2
defense response	1
G protein-coupled receptor activity	1
signal transduction	1
phospholipase C activator activity	1
anterograde trans-synaptic signaling	1
learning or memory	1
visual behavior	1
associative learning	1
vascular process in circulatory system	1
blood circulation	1
regulation of vasoconstriction	1
vasoconstriction	1
positive regulation of multicellular organismal process	1
modulation of chemical synaptic transmission	1
response to histamine	1
cellular response to nitrogen compound	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
Gq/11-coupled serotonin receptor activity	1
phospholipase C-activating G protein-coupled receptor signaling pathway	1
G protein-coupled serotonin receptor signaling pathway	1
G protein-coupled amine receptor activity	1
histamine binding	1
transmembrane signaling receptor activity	1
cytoplasm	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1
cell junction	1

Protein interactions and networks

STRING

850 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HRH1	GNAQ	P50148	978
HRH1	TRPV1	Q8NER1	827
HRH1	HDC	P19113	798
HRH1	IL31	Q6EBC2	657
HRH1	HRH4	Q9H3N8	579
HRH1	HRH2	P25021	576
HRH1	TAC1	P20366	571
HRH1	IL13	P35225	548
HRH1	HRH3	Q9Y5N1	547
HRH1	PRKAA1	Q13131	547
HRH1	SLC6A4	P31645	523
HRH1	HNMT	P50135	522
HRH1	HTR1A	P08908	515
HRH1	RHO	P08100	507
HRH1	HTR2A	P28223	504

IntAct

38 interactions, top by confidence:

A	B	Type	Score
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
KCNE3	RIOK3	psi-mi:“MI:0914”(association)	0.530
SH3GL2	HRH1	psi-mi:“MI:0915”(physical association)	0.400
HRH1	SH3GL1	psi-mi:“MI:0915”(physical association)	0.400
HRH1	SH3GL3	psi-mi:“MI:0915”(physical association)	0.400
	HRH1	psi-mi:“MI:0915”(physical association)	0.400
RAMP1	HRH1	psi-mi:“MI:0915”(physical association)	0.400
HRH1	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	HRH1	psi-mi:“MI:0915”(physical association)	0.400
HRH1	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
ATP6V0A1	HRH1	psi-mi:“MI:0915”(physical association)	0.370
CNBP	HRH1	psi-mi:“MI:0915”(physical association)	0.370
CD81	HRH1	psi-mi:“MI:0915”(physical association)	0.370
DHRS7	HRH1	psi-mi:“MI:0915”(physical association)	0.370
ADGRA3	HRH1	psi-mi:“MI:0915”(physical association)	0.370
WLS	HRH1	psi-mi:“MI:0915”(physical association)	0.370
LIMS2	HRH1	psi-mi:“MI:0915”(physical association)	0.370
MAT2B	HRH1	psi-mi:“MI:0915”(physical association)	0.370
SLC35B1	HRH1	psi-mi:“MI:0915”(physical association)	0.370
SLC43A2	HRH1	psi-mi:“MI:0915”(physical association)	0.370
YIPF3	HRH1	psi-mi:“MI:0915”(physical association)	0.370
ACKR3	PDE2A	psi-mi:“MI:0914”(association)	0.350
CXCR3	RIMOC1	psi-mi:“MI:0914”(association)	0.350
CXCR4	ESYT2	psi-mi:“MI:0914”(association)	0.350
GDPD5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
GPR17	C1QTNF9B	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): HRH1 (Co-localization), HRH1 (Affinity Capture-RNA), ATP6V0A1 (Two-hybrid), CNBP (Two-hybrid), CD81 (Two-hybrid), DHRS7 (Two-hybrid), GPR125 (Two-hybrid), WLS (Two-hybrid), LIMS2 (Two-hybrid), MAT2B (Two-hybrid), SLC35B1 (Two-hybrid), SLC43A2 (Two-hybrid), YIPF3 (Two-hybrid), HRH1 (Affinity Capture-Western), HRH1 (Reconstituted Complex)

ESM2 similar proteins: A2BGS3, A6NGA9, E7F594, O36364, O60478, O60883, O95800, O95838, P03208, P16849, P31389, P34590, P35367, P49219, Q03613, Q09351, Q09964, Q09965, Q14439, Q16950, Q16951, Q2KI97, Q3U3F9, Q5FVG1, Q5IXF8, Q5UAW9, Q60755, Q64017, Q66615, Q66H29, Q6P7G9, Q6SW98, Q6X632, Q7TSN5, Q7TSN6, Q80W35, Q80WT4, Q8BNQ3, Q8C206, Q8CIM5

Diamond homologs: A5A4K9, A5A4L1, C3ZQF9, O08725, O17239, O42179, O43193, O55040, O88319, O93603, P19020, P20789, P20905, P21917, P24628, P30989, P35367, P49683, P58826, P79291, Q09388, Q25188, Q28553, Q58CW4, Q5QD24, Q63384, Q7JQF1, Q8BZ39, Q8ITC7, Q90WY4, Q923Y8, Q92847, Q93126, Q95254, Q99P50, Q9ESQ4, Q9GZQ4, Q9HB89, Q9JJI5, Q9JJS7

SIGNOR signaling

53 interactions.

A	Effect	B	Mechanism
CAMK2A	down-regulates	HRH1	phosphorylation
PRKCA	down-regulates	HRH1	phosphorylation
PRKG1	down-regulates	HRH1	phosphorylation
PRKACA	down-regulates	HRH1	phosphorylation
HRH1	“up-regulates activity”	GNAS	binding
HRH1	“up-regulates activity”	GNAL	binding
HRH1	“up-regulates activity”	GNAI1	binding
HRH1	“up-regulates activity”	GNAI3	binding
HRH1	“up-regulates activity”	GNAO1	binding
HRH1	“up-regulates activity”	GNAZ	binding
HRH1	“up-regulates activity”	GNAQ	binding
HRH1	“up-regulates activity”	GNA14	binding
histamine	“up-regulates activity”	HRH1	“chemical activation”
epinastine	“down-regulates activity”	HRH1	“chemical inhibition”
Mequitazine	“down-regulates activity”	HRH1	“chemical inhibition”
bepotastine	“down-regulates activity”	HRH1	“chemical inhibition”
Olopatadine	“down-regulates activity”	HRH1	“chemical inhibition”
Carebastine	“down-regulates activity”	HRH1	“chemical inhibition”
desloratadine	“down-regulates activity”	HRH1	“chemical inhibition”
fexofenadine	“down-regulates activity”	HRH1	“chemical inhibition”
chlorphenamine	“down-regulates activity”	HRH1	“chemical inhibition”
diphenhydramine	“down-regulates activity”	HRH1	“chemical inhibition”
promethazine	“down-regulates activity”	HRH1	“chemical inhibition”
ketotifen	“down-regulates activity”	HRH1	“chemical inhibition”
azelastine	“down-regulates activity”	HRH1	“chemical inhibition”
Oxatomide	“down-regulates activity”	HRH1	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
G alpha (s) signalling events	5	12.2×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
receptor internalization	5	41.5×	4e-05
protein localization to plasma membrane	5	13.9×	3e-03
G protein-coupled receptor signaling pathway	8	7.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3223 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:11259239:A:C	S68R	0.999
3:11259241:C:A	S68R	0.999
3:11259241:C:G	S68R	0.999
3:11259255:A:C	D73A	0.998
3:11259255:A:T	D73V	0.998
3:11259386:A:C	S117R	0.998
3:11259388:T:A	S117R	0.998
3:11259388:T:G	S117R	0.998
3:11259491:T:A	W152R	0.998
3:11259491:T:C	W152R	0.998
3:11259632:T:C	F199L	0.998
3:11259634:C:A	F199L	0.998
3:11259634:C:G	F199L	0.998
3:11260307:T:C	F424L	0.998
3:11260309:C:A	F424L	0.998
3:11260309:C:G	F424L	0.998
3:11259254:G:C	D73H	0.997
3:11259255:A:G	D73G	0.997
3:11259256:C:A	D73E	0.997
3:11259256:C:G	D73E	0.997
3:11259368:A:C	S111R	0.997
3:11259370:C:A	S111R	0.997
3:11259370:C:G	S111R	0.997
3:11259411:G:C	R125P	0.997
3:11259509:T:A	W158R	0.997
3:11259509:T:C	W158R	0.997
3:11259642:C:G	P202R	0.997
3:11260319:T:A	W428R	0.997
3:11260319:T:C	W428R	0.997
3:11260417:C:A	N460K	0.997

dbSNP variants (sampled 300 via entrez): RS1000008364 (3:11150838 A>T), RS1000032945 (3:11228773 G>A,T), RS1000047411 (3:11239398 G>C), RS1000064204 (3:11190765 C>G,T), RS1000066406 (3:11138211 A>G), RS1000073605 (3:11181528 T>A,C,G), RS1000086134 (3:11236611 A>G), RS1000138927 (3:11182427 C>T), RS1000208825 (3:11196281 C>T), RS1000219045 (3:11245360 A>G), RS1000318364 (3:11202619 A>G,T), RS1000321277 (3:11242187 A>G), RS1000344888 (3:11223616 A>G), RS1000348350 (3:11185399 C>T), RS1000353851 (3:11202390 G>A)

Disease associations

OMIM: gene MIM:600167 | disease phenotypes: MIM:181500

GenCC curated gene-disease

Mondo (1): schizophrenia (MONDO:0005090)

Orphanet (1): NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0100753	Schizophrenia

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL231 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

268 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 579,627 (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
CHEMBL1000	CETIRIZINE	4	26,030
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1065	METHYSERGIDE	4	8,455
CHEMBL1071	OXAPROZIN	4	51,044
CHEMBL1078261	PROPIVERINE	4	4,890
CHEMBL1085	ACETOPHENAZINE	4	5,134
CHEMBL109	VALPROIC ACID	4	65,937
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL1101	BIPERIDEN	4	11,044
CHEMBL1108	DROPERIDOL	4	16,888
CHEMBL111	RIMONABANT	4	15,726
CHEMBL1112	ARIPIPRAZOLE	4	24,205
CHEMBL1113	AMOXAPINE	4	20,128
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1123	DICYCLOMINE	4	8,691
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1172	DESLORATADINE	4	19,720
CHEMBL1175	DULOXETINE	4	28,527
CHEMBL1189432	OLOPATADINE	4
CHEMBL1189679	PALONOSETRON	4
CHEMBL1194666	DIETHYLPROPION	4
CHEMBL1200406	DIMENHYDRINATE	4
CHEMBL1200492	NEFAZODONE HYDROCHLORIDE	4
CHEMBL1200618	FEXOFENADINE HYDROCHLORIDE	4
CHEMBL1200809	AZELASTINE HYDROCHLORIDE	4
CHEMBL1201	THIOTHIXENE	4
CHEMBL1201010	FLUDROCORTISONE ACETATE	4
CHEMBL1201027	GLYCOPYRRONIUM BROMIDE	4

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs901865	Toxicity	3	desloratadine	sedation;Urticaria

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs901865	HRH1	3	3.00	1	desloratadine
rs13064530	HRH1		0.00	0
rs1552498	HRH1		0.00	0
rs17034063	HRH1		0.00	0
rs2606731	HRH1		0.00	0
rs346076	HRH1		0.00	0
rs346070	HRH1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Histamine receptors

Most potent curated ligand interactions (91 total), top 25:

Ligand	Action	Affinity	Parameter
clemastine	Antagonist	10.31	pKi
cyproheptadine	Antagonist	10.2	pKi
doxepin	Antagonist	10.0	pKi
asenapine	Antagonist	9.8	pKi
promethazine	Antagonist	9.62	pKi
clozapine	Antagonist	9.6	pKi
amitriptyline	Antagonist	9.3	pKi
zotepine	Antagonist	9.2	pKi
olanzapine	Antagonist	9.2	pKi
alimemazine	Antagonist	9.14	pKi
[3H]pyrilamine	Inverse agonist	9.1	pKd
desloratadine	Antagonist	9.01	pKi
mepyramine	Inverse agonist	9.0	pKi
triprolidine	Antagonist	9.0	pKi
[11C]doxepin	Antagonist	9.0	pKd
azelastine	Antagonist	8.9	pKi
(-)-trans-H2-PAT	Antagonist	8.8	pKi
quetiapine	Antagonist	8.7	pKi
hydroxyzine	Antagonist	8.7	pKi
(+)-chlorpheniramine	Antagonist	8.6	pKi
ketotifen	Antagonist	8.6	pKi
(±)-trans-H2-PAT	Antagonist	8.6	pKi
astemizole	Antagonist	8.52	pKi
(R)-cetirizine	Inverse agonist	8.5	pKi
chlorprothixene	Antagonist	8.43	pKi

Binding affinities (BindingDB)

104 measured of 168 human assays (215 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carboxamide	KI	0.07 nM	US-9132134: Methods for treating GI tract disorders
NSC_104911	KI	0.1 nM
(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(furan-3-yl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester	EC50	0.3 nM
2-Chlor-11-(2-dimethylaminoaethoxy)-dibenzo(b,f)-thiepin	KI	0.5 nM
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine	KI	0.6 nM
Vistaril	KI	1 nM
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine	KI	1.4 nM
5-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-6-chloro-1,3-dihydro-indol-2-one	KI	1.9 nM
4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-1-(4-fluoro-phenyl)-butan-1-one;propionate(HCl)	KI	2.92 nM
8-[4-(4-fluorophenyl)-4-keto-butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	KI	2.94 nM	US-9359372: Hexahydrodibenzo[a,g]quinolizine compound, preparation method thereof, pharmaceutical composition and use thereof
(S)-mianserin	KI	3 nM
Cetirizine (+) isomer	KI	3.16 nM
NSC_55482	KI	3.2 nM
ATR	IC50	3.2 nM	US-9333195: Quinuclidine derivatives and medicinal compositions containing the same
ucb 29992, (R)	KI	5.01 nM
CAS_2830867	KI	6 nM
2-(p-bromo-alpha-(2-dimethylaminoethyl)benzyl)pyridine	KI	6.06 nM
Allegra	KI	10 nM
CAS_44450213	KI	10 nM
(S)-2-((S)-(2,3-dihydrobenzofuran-7-yloxy)(phenyl)methyl)morpholine	KI	10 nM
NSC_44450185	KI	10 nM
CAS_44450211	KI	10 nM
NSC_44449768	KI	10 nM
Dibencycladine	KI	12 nM
3-(9,10-dihydroanthracen-9-yl)-N-methylpropan-1-amine	KI	13 nM
1-[3-(2-methylsulfonylphenothiazin-10-yl)propyl]piperidine-4-carboxylic acid	KI	14 nM	US-9132134: Methods for treating GI tract disorders
9,10-dihydroanthracene(DHA), 1a	KI	20 nM
3-(9,10-dihydroanthracen-9-yl)-N,N-dimethylpropan-1-amine	KI	22 nM
2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]piperidin-1-yl]ethanol	IC50	25 nM	US-10106522: Benzimidazole derivatives as antihistamine agents
(S)-2-((S)-(4-chloro-2-methoxyphenoxy)(phenyl)methyl)morpholine	KI	26 nM
3-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]piperidin-1-yl]propan-1-ol	IC50	28 nM	US-10106522: Benzimidazole derivatives as antihistamine agents
3-(9,10-Dihydro-anthracen-9-yl)-propylamine	KI	32 nM
1-(4-{3-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone	KI	33 nM
(9,10-Dihydro-anthracen-9-ylmethyl)-methyl-amine	KI	52 nM
2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]piperidin-1-yl]ethyl acetate	IC50	54 nM	US-10106522: Benzimidazole derivatives as antihistamine agents
cid_3396	KI	56 nM
5-(1-methylpiperidylidene-4)-5H-dibenzo(a,d)cyclopheptene	KI	59 nM
ucb 29993, (S)	KI	63.1 nM
2-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-5-ethyl-4-(2-phenoxyethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one	KI	80 nM
9,10-dihydroanthracene(DHA), 2c	KI	84 nM
NSC_40589	KI	85 nM
9,10-dihydroanthracene(DHA), 2b	KI	92 nM
1-(2-ethoxyethyl)-2-[1-(2-methoxyethyl)piperidin-4-yl]benzimidazole	IC50	93 nM	US-10106522: Benzimidazole derivatives as antihistamine agents
2-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one	KI	96 nM
Cetirizine (-) isomer	KI	100 nM
2-[1-[2-(2-ethoxyethoxy)ethyl]piperidin-4-yl]-1-(2-ethoxyethyl)benzimidazole	IC50	115 nM	US-10106522: Benzimidazole derivatives as antihistamine agents
2-[4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol;hydrochloride	KI	146 nM
ethyl 2-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]piperidin-1-yl]ethoxy]acetate	IC50	169 nM	US-10106522: Benzimidazole derivatives as antihistamine agents
2-[4-[1-(pyridin-2-ylmethyl)benzimidazol-2-yl]piperidin-1-yl]ethanol	IC50	175 nM	US-10106522: Benzimidazole derivatives as antihistamine agents
methyl 2-[2-[4-[1-(2-phenoxyethyl)benzimidazol-2-yl]piperidin-1-yl]ethoxy]acetate	IC50	195 nM	US-10106522: Benzimidazole derivatives as antihistamine agents

ChEMBL bioactivities

2346 potent at pChembl≥5 of 2524 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.85	IC50	0.014	nM	PYRILAMINE
10.40	Kd	0.03981	nM	CHEMBL2146802
10.31	Ki	0.049	nM	CLEMASTINE
10.18	Ki	0.066	nM	DOXEPIN
10.06	Kd	0.087	nM	OLANZAPINE
10.00	Kd	0.1	nM	CHEMBL2146806
10.00	Kd	0.1	nM	CHEMBL1767136
10.00	Kd	0.1	nM	CHEMBL5284242
10.00	Ki	0.1	nM	CHEMBL1767137
9.88	Kd	0.1318	nM	CHEMBL5275284
9.86	Ki	0.138	nM	KETOTIFEN
9.80	Kd	0.1585	nM	CHEMBL5272464
9.80	Ki	0.1585	nM	KETOTIFEN
9.80	Ki	0.1585	nM	CHEMBL1767136
9.80	Ki	0.1585	nM	CHEMBL1767138
9.79	Ki	0.1622	nM	CHEMBL1767136
9.76	Ki	0.175	nM	MIANSERIN
9.75	Ki	0.1778	nM	E-DOXEPIN
9.75	Ki	0.1778	nM	DOXEPIN
9.74	Kd	0.182	nM	CHEMBL5282336
9.72	Ki	0.19	nM	CLOROTEPINE
9.70	Kd	0.1995	nM	AZELASTINE
9.70	Kd	0.1995	nM	CHEMBL4059750
9.70	Kd	0.1995	nM	CHEMBL4060529
9.70	Kd	0.1995	nM	CHEMBL5273244
9.70	Ki	0.1995	nM	CHEMBL1767141
9.60	Kd	0.2512	nM	CHEMBL2146801
9.60	Ki	0.2512	nM	CHEMBL2146801
9.60	Ki	0.2512	nM	DOXEPIN
9.60	Kd	0.2512	nM	CHEMBL5270515
9.60	Ki	0.2512	nM	E-DOXEPIN
9.60	Ki	0.2512	nM	CHEMBL1767134
9.60	Ki	0.2512	nM	CHEMBL1767149
9.58	Kd	0.263	nM	CHEMBL4084325
9.52	Ki	0.3	nM	CHEMBL1090527
9.50	Kd	0.3162	nM	CHEMBL2146809
9.50	Kd	0.3162	nM	CHEMBL2146807
9.50	Kd	0.3162	nM	CHEMBL2146805
9.50	Ki	0.3162	nM	CHEMBL2146809
9.50	Ki	0.3162	nM	CHEMBL2208424
9.50	Kd	0.3162	nM	CHEMBL5276489
9.50	Ki	0.3162	nM	CHEMBL1767140
9.50	Ki	0.3162	nM	CHEMBL1767154
9.48	Ki	0.334	nM	PROMETHAZINE
9.46	Ki	0.3467	nM	CHEMBL2146805
9.46	Kd	0.3467	nM	CHEMBL4098917
9.45	Ki	0.3548	nM	CHEMBL2146484
9.43	Ki	0.37	nM	BENZTROPINE
9.40	Ki	0.3981	nM	CHEMBL2146806
9.40	EC50	0.4	nM	CLOZAPINE

PubChem BioAssay actives

1967 with measured affinity, of 5612 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
Pyrilamine	1285632: Displacement of [3H]pyrilamine from human recombinant histamine H1 receptor expressed in HEK293 cells	ic50	<0.0001	uM
2-[[(2R)-1-butylpyrrolidin-2-yl]methyl]-4-[(4-chlorophenyl)methyl]phthalazin-1-one	687274: Antagonist activity against human CHO cells H1 receptor at 100 nM after 30 mins by FLIPR assay	kd	<0.0001	uM
Olanzapine	692513: Binding affinity to human histamine H1 receptor	kd	0.0001	uM
4-[(4-chlorophenyl)methyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]phthalazin-1-one	687274: Antagonist activity against human CHO cells H1 receptor at 100 nM after 30 mins by FLIPR assay	kd	0.0001	uM
N-[2-[(2R)-2-[[4-[(4-chlorophenyl)methyl]-1-oxophthalazin-2-yl]methyl]pyrrolidin-1-yl]ethyl]-2-methylpropanamide;2,2,2-trifluoroacetic acid	1957461: Antagonist potency at human H1 receptor	kd	0.0001	uM
N-[2-[(2R)-2-[[4-[(4-chlorophenyl)methyl]-1-oxophthalazin-2-yl]methyl]pyrrolidin-1-yl]ethyl]-4-methoxy-N-methylbutanamide;2,2,2-trifluoroacetic acid	1957461: Antagonist potency at human H1 receptor	kd	0.0001	uM
4-[(4-methoxyphenyl)methyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]phthalazin-1-one	591512: Antagonist activity at human recombinant histamine H1 receptor expressed in intact CHO cells assessed as inhibition of histamine-induced cellular calcium mobilization by FLIPR assay	ki	0.0001	uM
2-[[(2R)-1-butylpyrrolidin-2-yl]methyl]-4-[(4-chlorophenyl)methyl]pyrido[3,4-d]pyridazin-1-one	687274: Antagonist activity against human CHO cells H1 receptor at 100 nM after 30 mins by FLIPR assay	kd	0.0001	uM
1-(3-chloro-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)-4-methylpiperazine	517793: Displacement of [3H]prozosin from human cloned histamine H1 receptor expressed in CHO cells	ki	0.0002	uM
N-[4-[4-(6-butylquinolin-8-yl)oxypiperidin-1-yl]butyl]propane-1-sulfonamide;dihydrochloride	1464934: Antagonist activity at human histamine H1 receptor expressed in CHO cells assessed as inhibition of histamine-induced intracellular calcium mobilization at 100 nM pretreated for 30 mins followed by histamine addition measured for 1 min by Fluo-4-AM dye based FLIPR method	kd	0.0002	uM
N-[2-[(2R)-2-[[4-[(4-chlorophenyl)methyl]-1-oxophthalazin-2-yl]methyl]pyrrolidin-1-yl]ethyl]-4-methoxybutanamide;dihydrochloride	1464934: Antagonist activity at human histamine H1 receptor expressed in CHO cells assessed as inhibition of histamine-induced intracellular calcium mobilization at 100 nM pretreated for 30 mins followed by histamine addition measured for 1 min by Fluo-4-AM dye based FLIPR method	kd	0.0002	uM
N-[2-[(2R)-2-[[4-[(4-chlorophenyl)methyl]-1-oxophthalazin-2-yl]methyl]pyrrolidin-1-yl]ethyl]-4-methoxybutanamide;2,2,2-trifluoroacetic acid	1957461: Antagonist potency at human H1 receptor	kd	0.0002	uM
Azelastine	1331191: Antagonist activity at human Histamine H1 receptor expressed in CHO cells assessed as inhibition of histamine-induced calcium flux at 100 nM preincubated for 30 mins followed by histamine addition by Fluo-4-AM dye based FLIPR assay	kd	0.0002	uM
4-[(2R)-2-[[4-[(4-chlorophenyl)methyl]-1-oxophthalazin-2-yl]methyl]pyrrolidin-1-yl]-N-propylbutanamide;hydrochloride	1957461: Antagonist potency at human H1 receptor	kd	0.0002	uM
N-[2-[(2R)-2-[[4-[(4-chlorophenyl)methyl]-1-oxophthalazin-2-yl]methyl]pyrrolidin-1-yl]ethyl]-2-methoxyacetamide;2,2,2-trifluoroacetic acid	1957461: Antagonist potency at human H1 receptor	kd	0.0002	uM
Doxepin	632679: Displacement of [3H]mepyramine from human histamine H1 receptor expressed in HEK293 cells after 1 to 1.5 hrs by scintillation counting	ki	0.0002	uM
Ketotifen	537324: Antagonist activity against human histamine H1 receptor expressed in CHO cells by FLIPR assay	ki	0.0002	uM
4-[(4-hydroxyphenyl)methyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]phthalazin-1-one	591512: Antagonist activity at human recombinant histamine H1 receptor expressed in intact CHO cells assessed as inhibition of histamine-induced cellular calcium mobilization by FLIPR assay	ki	0.0002	uM
4-[(4-methylphenyl)methyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]phthalazin-1-one	591512: Antagonist activity at human recombinant histamine H1 receptor expressed in intact CHO cells assessed as inhibition of histamine-induced cellular calcium mobilization by FLIPR assay	ki	0.0002	uM
(3E)-3-(6H-benzo[c][1]benzoxepin-11-ylidene)-N,N-dimethylpropan-1-amine	1912446: Displacement of [3H]mepyramine from human H1R expressed in HEK293T cell homogenates incubated for 1 hr by radioligand binding assay based liquid scintillation counter	ki	0.0002	uM
6-butyl-8-[1-(3-ethylsulfonylpropyl)piperidin-4-yl]oxyquinoline;dihydrochloride	1464934: Antagonist activity at human histamine H1 receptor expressed in CHO cells assessed as inhibition of histamine-induced intracellular calcium mobilization at 100 nM pretreated for 30 mins followed by histamine addition measured for 1 min by Fluo-4-AM dye based FLIPR method	kd	0.0003	uM
4-[(4-chlorophenyl)methyl]-2-[2-(dimethylamino)ethyl]phthalazin-1-one	591512: Antagonist activity at human recombinant histamine H1 receptor expressed in intact CHO cells assessed as inhibition of histamine-induced cellular calcium mobilization by FLIPR assay	ki	0.0003	uM
N-[2-[(2R)-2-[[4-[(4-chlorophenyl)methyl]-1-oxophthalazin-2-yl]methyl]pyrrolidin-1-yl]ethyl]propanamide;2,2,2-trifluoroacetic acid	1957461: Antagonist potency at human H1 receptor	kd	0.0003	uM
N-[2-[(2R)-2-[[4-[(4-chlorophenyl)methyl]-1-oxophthalazin-2-yl]methyl]pyrrolidin-1-yl]ethyl]cyclopentanecarboxamide;2,2,2-trifluoroacetic acid	1957461: Antagonist potency at human H1 receptor	kd	0.0003	uM
6-butyl-8-[1-(3-tert-butylsulfonylpropyl)piperidin-4-yl]oxyquinoline	1464934: Antagonist activity at human histamine H1 receptor expressed in CHO cells assessed as inhibition of histamine-induced intracellular calcium mobilization at 100 nM pretreated for 30 mins followed by histamine addition measured for 1 min by Fluo-4-AM dye based FLIPR method	kd	0.0003	uM
2-[6-fluoro-3-[(1R)-1-(1,3-thiazol-2-yl)ethyl]-1H-inden-2-yl]-N,N-dimethylethanamine	474299: Binding affinity at histamine H1 receptor	ki	0.0003	uM
4-[(4-fluorophenyl)methyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]phthalazin-1-one	591512: Antagonist activity at human recombinant histamine H1 receptor expressed in intact CHO cells assessed as inhibition of histamine-induced cellular calcium mobilization by FLIPR assay	ki	0.0003	uM
4-[(3,4-difluorophenyl)methyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]phthalazin-1-one	591512: Antagonist activity at human recombinant histamine H1 receptor expressed in intact CHO cells assessed as inhibition of histamine-induced cellular calcium mobilization by FLIPR assay	ki	0.0003	uM
4-[(4-chlorophenyl)methyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]phthalazin-1-one	591512: Antagonist activity at human recombinant histamine H1 receptor expressed in intact CHO cells assessed as inhibition of histamine-induced cellular calcium mobilization by FLIPR assay	ki	0.0003	uM
7-[[(2R)-1-butylpyrrolidin-2-yl]methyl]-5-[(4-chlorophenyl)methyl]pyrido[2,3-d]pyridazin-8-one	687274: Antagonist activity against human CHO cells H1 receptor at 100 nM after 30 mins by FLIPR assay	kd	0.0003	uM
3-[(2S)-4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxybutoxy]benzonitrile	719511: Displacement of [3H]-pyrilamine from human histamine H1 receptor expressed in recombinant CHOK1 cells after 1 hr	ki	0.0003	uM
4-[(4-chlorophenyl)methyl]-2-[[(2R)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]pyrido[3,4-d]pyridazin-1-one	687266: Antagonist activity at human H1 receptor expressed in CHO cells assessed as inhibition of calcium mobilization by FLIPR assay	ki	0.0003	uM
4-[(4-chlorophenyl)methyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]pyrido[3,4-d]pyridazin-1-one	687266: Antagonist activity at human H1 receptor expressed in CHO cells assessed as inhibition of calcium mobilization by FLIPR assay	ki	0.0003	uM
8-[(4-chlorophenyl)methyl]-6-[[(2R)-1-methylpyrrolidin-2-yl]methyl]pyrido[2,3-d]pyridazin-5-one	687266: Antagonist activity at human H1 receptor expressed in CHO cells assessed as inhibition of calcium mobilization by FLIPR assay	ki	0.0003	uM
13-chloro-2-(1-ethylpiperidin-4-ylidene)-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene	1569605: Displacement of [3H]mepyramine from N-terminal HA-tagged H1R (unknown origin) expressed in HEK293T cells measured after 4 hrs by microbeta scintillation counting method	ki	0.0004	uM
N,N-dimethyl-2-[3-[(1R)-1-pyridin-2-ylethyl]-1H-inden-2-yl]ethanamine	431637: Displacement of [3H]pyrilamine from human histamine H1 receptor expressed in CHO Flp-In cells by liquid scintillation counting	ki	0.0004	uM
N-[4-[4-(6-butylquinolin-8-yl)oxypiperidin-1-yl]butyl]methanesulfonamide;dihydrochloride	1464934: Antagonist activity at human histamine H1 receptor expressed in CHO cells assessed as inhibition of histamine-induced intracellular calcium mobilization at 100 nM pretreated for 30 mins followed by histamine addition measured for 1 min by Fluo-4-AM dye based FLIPR method	kd	0.0004	uM
6-butyl-8-[1-(3-propan-2-ylsulfonylpropyl)piperidin-4-yl]oxyquinoline;dihydrochloride	1464934: Antagonist activity at human histamine H1 receptor expressed in CHO cells assessed as inhibition of histamine-induced intracellular calcium mobilization at 100 nM pretreated for 30 mins followed by histamine addition measured for 1 min by Fluo-4-AM dye based FLIPR method	kd	0.0004	uM
(E)-but-2-enedioic acid;13-chloro-2-(1-methylpiperidin-4-ylidene)-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene	1569605: Displacement of [3H]mepyramine from N-terminal HA-tagged H1R (unknown origin) expressed in HEK293T cells measured after 4 hrs by microbeta scintillation counting method	ki	0.0004	uM
5-[(4-chlorophenyl)methyl]-7-[[(2R)-1-methylpyrrolidin-2-yl]methyl]pyrido[2,3-d]pyridazin-8-one	687266: Antagonist activity at human H1 receptor expressed in CHO cells assessed as inhibition of calcium mobilization by FLIPR assay	ki	0.0004	uM
N,N-dimethyl-1-[(2S,4R,6R)-3-oxatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),7,9,11,14,16-hexaen-4-yl]methanamine	239091: Inhibition of [3H]pyrilamine binding to human Histamine H1 receptor	ki	0.0004	uM
3-(9,10-dihydroanthracen-9-yl)-N,N-dimethylpropan-1-amine	1799359: Radioligand Binding Assay from Article 10.1016/j.bmc.2009.08.016: “Synthesis, structure-affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: structural factors contributing to selectivity.”	ki	0.0005	uM
4-[(2R)-2-[[4-[(4-chlorophenyl)methyl]-1-oxophthalazin-2-yl]methyl]pyrrolidin-1-yl]-N-(2-methoxyethyl)butanamide;hydrochloride	1957461: Antagonist potency at human H1 receptor	kd	0.0005	uM
N-[2-[(2R)-2-[[4-[(4-chlorophenyl)methyl]-1-oxophthalazin-2-yl]methyl]pyrrolidin-1-yl]ethyl]-3-methoxypropanamide;formic acid	1957461: Antagonist potency at human H1 receptor	kd	0.0005	uM
N-[4-[4-(6-butylquinolin-8-yl)oxypiperidin-1-yl]butyl]ethanesulfonamide;dihydrochloride	1464934: Antagonist activity at human histamine H1 receptor expressed in CHO cells assessed as inhibition of histamine-induced intracellular calcium mobilization at 100 nM pretreated for 30 mins followed by histamine addition measured for 1 min by Fluo-4-AM dye based FLIPR method	kd	0.0005	uM
1-[(2S,4R)-17-fluoro-3-oxa-13-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),7,9,11,15,17-hexaen-4-yl]-N,N-dimethylmethanamine	239091: Inhibition of [3H]pyrilamine binding to human Histamine H1 receptor	ki	0.0005	uM
1-[(4-fluorophenyl)methyl]-2-(1-methylpiperidin-3-yl)benzimidazole	638777: Antagonist activity at histamine H1 receptor	ki	0.0005	uM
4-[(3-fluorophenyl)methyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]phthalazin-1-one	591512: Antagonist activity at human recombinant histamine H1 receptor expressed in intact CHO cells assessed as inhibition of histamine-induced cellular calcium mobilization by FLIPR assay	ki	0.0005	uM
1-[2-[4-[5-chloro-1-(4-fluorophenyl)indol-3-yl]piperidin-1-yl]ethyl]imidazolidin-2-one	517793: Displacement of [3H]prozosin from human cloned histamine H1 receptor expressed in CHO cells	ki	0.0005	uM
4-[(4-chlorophenyl)methyl]-2-[[(2R)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]phthalazin-1-one	687266: Antagonist activity at human H1 receptor expressed in CHO cells assessed as inhibition of calcium mobilization by FLIPR assay	ki	0.0005	uM

CTD chemical–gene interactions

90 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Histamine	decreases abundance, affects binding, decreases expression, decreases reaction, affects cotreatment (+10 more)	9
Calcium	decreases reaction, increases import, increases export, increases reaction, affects binding (+2 more)	5
Diphenhydramine	decreases reaction, decreases response to substance, increases reaction, affects binding, decreases activity (+1 more)	5
Pyrilamine	affects binding, decreases reaction, affects reaction, decreases response to substance, increases reaction (+1 more)	5
Triprolidine	decreases abundance, increases export, increases metabolic processing, decreases response to substance, affects binding (+6 more)	5
sodium arsenite	increases expression, affects methylation	3
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, affects methylation	3
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
Olanzapine	affects cotreatment, increases response to substance, affects binding	2
Chlorpheniramine	affects binding, decreases activity	2
Hydroxyzine	affects binding, decreases activity	2
Nickel	increases expression	2
Promethazine	affects binding, decreases activity, increases activity, decreases reaction	2
Valproic Acid	decreases methylation, affects expression	2
Cyclosporine	increases expression, decreases methylation	2
Aflatoxin B1	increases expression, increases methylation	2
Cetirizine	affects binding, decreases activity	2
Cadmium Chloride	increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
azatadine	affects binding, decreases activity	1
diphenylpyraline	affects binding, increases activity, decreases reaction	1
tributyltin	decreases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
azelastine	affects binding	1
manganese chloride	decreases methylation	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	decreases methylation	1
cupric oxide	increases expression	1
fluorescein isothiocyanate bovine serum albumin	affects reaction, increases transport	1

ChEMBL screening assays

847 unique, capped per target: 716 binding, 113 functional, 17 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000174	Binding	Binding affinity to histamine H1 receptor	Synthesis and evaluation of dibenzothiazepines: a novel class of selective cannabinoid-1 receptor inverse agonists. — J Med Chem
CHEMBL1038010	Functional	Antagonist activity at histamine H1 receptor in human SK-N-SH cells assessed as histamine-induced maximum intracellular calcium spike at phase 1 treated 10 to 15 seconds before histamine challenge	Synthesis and biological activity of 5-styryl and 5-phenethyl-substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles. — Bioorg Med Chem Lett
CHEMBL3774136	ADMET	Inhibition of histamine H1 receptor (unknown origin) assessed as inhibition of histamine-induced beta-arrestin internalization preincubated at 10 nM for 3 hrs followed by addition of 0.25 uM histamine measured after 2 hrs by PathHunter cell	Discovery, Optimization, and Characterization of Novel Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection. — J Med Chem

Cellosaurus cell lines

9 cell lines: 4 cancer cell line, 2 transformed cell line, 2 spontaneously immortalized cell line, 1 undefined cell line type

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

Cellosaurus	Name	Category	Sex
CVCL_D7RF	Ubigene A-549 HRH1 KO	Cancer cell line	Male
CVCL_D8ML	Ubigene HCT 116 HRH1 KO	Cancer cell line	Male
CVCL_E0EE	Ubigene HeLa HRH1 KO	Cancer cell line	Female
CVCL_H370	293/H1	Transformed cell line	Female
CVCL_KX83	PathHunter CHO-K1 HRH1 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_RU13	Chem-3 HRH1	Undefined cell line type
CVCL_XA28	GeneBLAzer H1-NFAT-bla HEK 293T	Transformed cell line	Female
CVCL_XD06	CHO-HRH1	Spontaneously immortalized cell line	Female
CVCL_YK49	U2OS HRH1 HiTSeeker	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety