HRH3

Summary

HRH3 (histamine receptor H3, HGNC:5184) is a protein-coding gene on chromosome 20q13.33, encoding Histamine H3 receptor (Q9Y5N1). The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system.

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. This gene encodes one of the histamine receptors (H3) which belongs to the family 1 of G protein-coupled receptors. It is an integral membrane protein and can regulate neurotransmitter release. This receptor can also increase voltage-dependent calcium current in smooth muscles and innervates the blood vessels and the heart in cardiovascular system.

Source: NCBI Gene 11255 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 50 total — 1 likely-pathogenic
• Druggable target: yes — 172 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_007232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5184
Approved symbol	HRH3
Name	histamine receptor H3
Location	20q13.33
Locus type	gene with protein product
Status	Approved
Aliases	GPCR97
Ensembl gene	ENSG00000101180
Ensembl biotype	protein_coding
OMIM	604525
Entrez	11255

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000317393, ENST00000340177, ENST00000932927

RefSeq mRNA: 1 — MANE Select: NM_007232 NM_007232

CCDS: CCDS13493

Canonical transcript exons

ENST00000340177 — 3 exons

Exon	Start	End
ENSE00000663205	62218491	62218657
ENSE00001390351	62214960	62216926
ENSE00001847733	62219721	62220278

Expression profiles

Bgee: expression breadth broad, 79 present calls, max score 90.99.

FANTOM5 (CAGE): breadth broad, TPM avg 2.7430 / max 471.1231, expressed in 234 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188249	1.9035	196
188247	0.6650	133
188248	0.1745	63

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
putamen	UBERON:0001874	90.99	gold quality
nucleus accumbens	UBERON:0001882	90.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.06	gold quality
caudate nucleus	UBERON:0001873	89.13	gold quality
cerebellar hemisphere	UBERON:0002245	88.64	gold quality
cerebellar cortex	UBERON:0002129	88.49	gold quality
cerebellum	UBERON:0002037	87.01	gold quality
anterior cingulate cortex	UBERON:0009835	86.90	gold quality
cingulate cortex	UBERON:0003027	86.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.59	gold quality
right frontal lobe	UBERON:0002810	84.81	gold quality
hypothalamus	UBERON:0001898	84.73	gold quality
Brodmann (1909) area 9	UBERON:0013540	81.77	gold quality
prefrontal cortex	UBERON:0000451	81.55	gold quality
buccal mucosa cell	CL:0002336	81.45	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.30	gold quality
telencephalon	UBERON:0001893	81.14	gold quality
frontal cortex	UBERON:0001870	80.86	gold quality
neocortex	UBERON:0001950	80.82	gold quality
tendon of biceps brachii	UBERON:0008188	79.74	gold quality
triceps brachii	UBERON:0001509	79.70	gold quality
amygdala	UBERON:0001876	79.70	gold quality
parotid gland	UBERON:0001831	79.67	gold quality
brain	UBERON:0000955	79.45	gold quality
gluteal muscle	UBERON:0002000	79.44	gold quality
forebrain	UBERON:0001890	79.38	gold quality
cerebral cortex	UBERON:0000956	78.93	gold quality
lateral nuclear group of thalamus	UBERON:0002736	77.86	gold quality
temporal lobe	UBERON:0001871	77.26	gold quality
primary visual cortex	UBERON:0002436	77.09	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.48

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYOD1

miRNA regulators (miRDB)

46 targeting HRH3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-143-5P	98.98	68.87	946
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-6895-3P	98.79	65.69	996
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-3188	98.58	65.60	878
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-3944-5P	98.50	67.55	997

Literature-anchored findings (GeneRIF, showing 40)

• Analogous to the effects of alpha(2)-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, H(3)R-mediated antiexocytotic effects could result from a decreased Ca(2+) influx into nerve endings (PMID:11752397)
• The structure of HRH3 has been determined and a missense mutation (Ala280Val) identified in a patient with Shy-Drager syndrome. (PMID:11956964)
• Molecular cloning of functionally distinct isoforms of the human histamine H(3) receptor (PMID:12069903)
• Densities of histamine H(3) receptor sites were significantly decreased in patient material. (PMID:12971961)
• absence of H3 receptor in human skin mast cells (PMID:15191551)
• “The human H(3)receptor gene suggested to consist of either 3 exons and 2 introns, or 4 exons and 3 introns, with …additional exon accounting for…8 additional carboxy(C)-terminal amino acids…in some human H(3) receptor sequences” (PMID:15665857)
• we describe the biological and chemical implications for developing H3 receptor antagonists and their therapeutic potential as disclosed through animal models of cognition, sleep, and obesity. (PMID:16565470)
• The purpose of this study was to identify the structural requirements for H3 antagonistic activity via quantitative structure-activity relationship (QSAR) studies and receptor modeling/docking techniques. (PMID:17561422)
• Histamine excites human enteric neurones and this effect involves histamine H1-4 receptors. (PMID:17627982)
• Data show that histamine regulates pancreatic carcinoma cell growth through H3 and H4 receptors. (PMID:18345506)
• H(3)R is localized mainly around submucosal glands and plays an important role in the secretion of submucosal glands in the nose. (PMID:18564330)
• role in neurogenic inflammation (PMID:18802338)
• D1-H3 receptor heteromers constitute unique devices that can direct dopaminergic and histaminergic signalling towards the MAPK pathway in a G(s)-independent and G(i)-dependent manner. (PMID:19413572)
• Histamine H3 receptors in the prefrontal cortex take part in the modulation of cognition, which is impaired in schizophrenic subjects and bipolar subjects with psychotic symptoms. (PMID:19413576)
• Modulation of PKCalpha by histamine receptors may be important in regulating cholangiocarcinoma growth. (PMID:19825989)
• This review outlines the relevance of the histaminergic system in controlling feeding behavior and evaluates the potential role of the histamine H3 receptor as a target for regulating obesity. (PMID:20864503)
• Data suggest that V-allele genotypes in the H3 receptor gene increase inactive receptors, enhancing inhibition of negative feedback mechanism on the H3 receptor and increasing histamine release, correlating with migraine attacks in susceptible patients. (PMID:21376262)
• Significant association of HRH3 with antipsychotic efficacy was detected. (PMID:21652606)
• The hydrophobic amino acids in putative helix 8 in carboxy-terminus of histamine H(3) receptor are involved in receptor-G-protein coupling. (PMID:21749919)
• mRNA expression of HRH-3 localized in large pigmented neurons is significantly decreased in the substantia nigra of Parkinson’s patients. (PMID:22118942)
• Histamine H3 receptor levels are unchanged in subcortical ischemic vascular dementia and mixed dementias in all brain areas studied. (PMID:22129936)
• [review] The H1, H2, and H3 receptors are all involved in recovery of neurological function when extracellular histamine is gradually increasing, after cerebral ischemia. (PMID:22860191)
• ZEL-H16 is a novel and potent nonimidazole agonist of H3R, which might serve as a pharmacological tool for future investigations or as possible therapeutic agent of H3R. (PMID:22870296)
• study identified novel functional properties in terms of voltage sensitivities and deactivation rates, which differed between the histamine hH3445, hH3365, and H4 receptors (PMID:22885137)
• the anatomical localization of Hreceptors suggests a complex interaction that could both enhance and inhibit dopaminergic neurotransmission; tt is conceivable that Hreceptors can moderate the development and maintenance of drug addiction. (PMID:23647606)
• In this review, we focus on the role of histamine and its receptors in the treatment of Alzheimer’s disease. (PMID:23677734)
• The A280V mutation reduces the signalling efficacy of the human H3 receptor; this effect may be relevant to the pathophysiology of disorders associated with the mutation (PMID:23713487)
• Report synthesis/functional characterization of imbutamine analogs as histamine H3 agonists. (PMID:24493592)
• The polymorphisms of HNMT and HRH3 were irrelevant with breast cancer in the present study. (PMID:24835231)
• Molecular modelling studies, including molecular dynamic simulations and calculation of Gibbs energy of solvation of hH3R and hH4R, were studied. (PMID:25098339)
• Decrease in histamine H3 receptor function was linked to epileptic activity in the hippocampus and temporal neocortex of patients with pharmacoresistant mesial temporal lobe epilepsy. (PMID:26915454)
• These findings for the first time screen out one SNP (rs3787429) of HRH3 gene that was significantly associated with CHF in Chinese Han population (PMID:26989676)
• results indicate that the single-point Y197C mutation, in the aminus region of TM5 of the hH3R445, does not affect the expression, ligand binding or signaling of the receptor (PMID:28126588)
• We detected high H3R expression in oligodendroglial cells from demyelination lesions in human samples of patients with MS, and validated a genetic association between an exonic single nucleotide polymorphism in HRH3 and susceptibility to multiple sclerosis. (PMID:29253893)
• These results indicate that in SH-SY5Y cells, hH3R445 and hH3R365 isoforms regulate in a differential manner the signaling pathways triggered by receptor activation. (PMID:29557708)
• Histamine, histamine H3 receptor, and alcohol use disorder. (PMID:30801695)
• These findings revealed that HRH3 serves an important role in the growth and metastasis of hepatocellular carcinomacells, which provides experimental evidence supporting the application of HRH3 as a potential therapeutic target in hepatocellular carcinoma treatment (PMID:31002350)
• Histamine H3 receptor gene variants associated with drug abuse in patients with cocaine use disorder. (PMID:33063610)
• Unraveling the venom chemistry with evidence for histamine as key regulator in the envenomation by caterpillar Automeris zaruma. (PMID:36091066)
• Recovery of the histamine H3 receptor activity lost in yeast cells through error-prone PCR and in vivo selection. (PMID:37752220)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hrh3	ENSMUSG00000039059
rattus_norvegicus	Hrh3	ENSRNOG00000061153

Paralogs (25): DRD4 (ENSG00000069696), 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), HRH1 (ENSG00000196639), GPR52 (ENSG00000203737), TAAR9 (ENSG00000237110)

Protein

Protein identifiers

Histamine H3 receptor — Q9Y5N1 (reviewed: Q9Y5N1)

Alternative names: G-protein coupled receptor 97

All UniProt accessions (2): Q9Y5N1, A0A0A0MR48

UniProt curated annotations — full annotation on UniProt →

Function. The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization.

Subcellular location. Cell membrane.

Tissue specificity. Expressed predominantly in the CNS, with the greatest expression in the thalamus and caudate nucleus. The various isoforms are mainly coexpressed in brain, but their relative expression level varies in a region-specific manner. Isoform 3 and isoform 7 are highly expressed in the thalamus, caudate nucleus and cerebellum while isoform 5 and isoform 6 show a poor expression. Isoform 5 and isoform 6 show a high expression in the amygdala, substantia nigra, cerebral cortex and hypothalamus. Isoform 7 is not found in hypothalamus or substantia nigra.

Miscellaneous. Does not bind to cimetidine and tripolidine. Shows modest affinity for thioperamide, imetit, N-alpha-methylhistamine and R(-)-alpha-methylhistamine. Isoform 4 is unable to bind to iodoproxyfan while isoforms 1 and 3 bind it with high affinity.

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

Isoforms (7)

UniProt ID	Names	Canonical?
Q9Y5N1-1	1	yes
Q9Y5N1-2	2
Q9Y5N1-3	3, H3S
Q9Y5N1-4	4
Q9Y5N1-5	5
Q9Y5N1-6	6
Q9Y5N1-7	7

RefSeq proteins (1): NP_009163* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR003980	Histamine_H3_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (48 total): helix 13, topological domain 8, transmembrane region 7, splice variant 6, compositionally biased region 3, region of interest 2, turn 2, chain 1, modified residue 1, glycosylation site 1, disulfide bond 1, sequence variant 1, sequence conflict 1, strand 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
7F61	X-RAY DIFFRACTION	2.6
8YN5	ELECTRON MICROSCOPY	2.7
8YUU	ELECTRON MICROSCOPY	2.7
8YN6	ELECTRON MICROSCOPY	2.77
8YN7	ELECTRON MICROSCOPY	2.77
8YN8	ELECTRON MICROSCOPY	2.77
8YUV	ELECTRON MICROSCOPY	3
9JEQ	ELECTRON MICROSCOPY	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5N1-F1	77.15	0.41

Antibody-complex structures (SAbDab): 5 — 8YN5, 8YN6, 8YUU, 8YUV, 9JEQ

Functional residue map

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

Post-translational modifications (1): 439

Disulfide bonds (1): 107–188

Glycosylation sites (1): 11

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-390650	Histamine receptors

MSigDB gene sets: 130 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEUROTRANSMITTER_TRANSPORT, TGACCTY_ERR1_Q2, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, SP1_Q2_01, GOBP_CELL_CELL_SIGNALING, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, MYOD_01, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_SECRETION, GOBP_SIGNAL_RELEASE, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_SYNAPTIC_SIGNALING

GO Biological Process (7): G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger (GO:0007187), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway (GO:0007197), chemical synaptic transmission (GO:0007268), neurotransmitter secretion (GO:0007269), 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 (5): plasma membrane (GO:0005886), dendrite (GO:0030425), synapse (GO:0045202), presynapse (GO:0098793), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Amine ligand-binding receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
cellular anatomical structure	2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1
G protein-coupled acetylcholine receptor signaling pathway	1
anterograde trans-synaptic signaling	1
neurotransmitter transport	1
chemical synaptic transmission	1
establishment of localization in cell	1
presynapse	1
signal release from synapse	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
synapse	1

Protein interactions and networks

STRING

1414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HRH3	HDC	P19113	791
HRH3	CLIC4	Q9Y696	770
HRH3	HNMT	P50135	720
HRH3	HRH2	P25021	679
HRH3	DRD1	P21728	658
HRH3	TPM3	P06753	612
HRH3	SLC16A8	O95907	588
HRH3	BCHE	P06276	575
HRH3	HIVEP2	P31629	548
HRH3	AQP1	P29972	547
HRH3	HRH1	P35367	547
HRH3	HRH4	Q9H3N8	537
HRH3	MCHR1	Q99705	512
HRH3	SIGMAR1	Q99720	506
HRH3	DRD2	P14416	505

IntAct

11 interactions, top by confidence:

A	B	Type	Score
	HRH3	psi-mi:“MI:0915”(physical association)	0.400
HRH3	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	HRH3	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	HRH3	psi-mi:“MI:0915”(physical association)	0.400
HRH3	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
RAMP1	HRH3	psi-mi:“MI:0915”(physical association)	0.400
HRH3	RAMP2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (5): ADORA2A (Affinity Capture-Western), ADORA2A (Reconstituted Complex), DRD2 (FRET), HRH3 (Affinity Capture-RNA), HRH3 (FRET)

ESM2 similar proteins: A0A287A2K5, F1MV99, O08858, O43193, O77808, O97772, P28646, P30098, P30552, P30553, P30796, P30872, P30873, P30937, P30938, P31391, P32239, P32300, P32307, P32745, P33533, P35346, P35370, P35377, P41143, P41146, P46095, P46627, P47748, P48044, P49660, P51651, P56481, P58406, P79266, P79292, Q49LX5, Q5D0K2, Q6W5G4, Q6YNI2

Diamond homologs: G4WMX4, O02662, O02664, O02813, O02835, O02836, O08892, O42179, O42385, O43193, O73810, O77408, O97512, P05363, P0C7U4, P0DQD5, P16177, P16610, P20905, P21452, P21555, P21918, P25115, P25929, P25931, P28285, P28566, P29371, P30098, P30548, P30549, P30731, P34992, P46626, P46636, P47800, P49146, P49683, P50391, P53454

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
HRH3	“up-regulates activity”	GNAI1	binding
HRH3	“up-regulates activity”	GNAI3	binding
HRH3	“up-regulates activity”	GNAO1	binding
histamine	“up-regulates activity”	HRH3	“chemical activation”
azelastine	“down-regulates activity”	HRH3	“chemical inhibition”
chlorphenamine	“down-regulates activity”	HRH3	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	42
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
155517	GRCh38/hg38 20q13.2-13.33(chr20:53236165-64284202)x3	Likely pathogenic

SpliceAI

705 predictions. Top by Δscore:

Variant	Effect	Δscore
20:62216926:CCTG:C	acceptor_loss	1.0000
20:62216927:C:CG	acceptor_loss	1.0000
20:62218487:TCACC:T	donor_loss	1.0000
20:62218488:CA:C	donor_loss	1.0000
20:62218489:A:AC	donor_gain	1.0000
20:62218489:A:T	donor_loss	1.0000
20:62218489:AC:A	donor_gain	1.0000
20:62218489:ACCG:A	donor_gain	1.0000
20:62218490:C:A	donor_loss	1.0000
20:62218490:C:CA	donor_gain	1.0000
20:62218490:CC:C	donor_gain	1.0000
20:62218490:CCG:C	donor_gain	1.0000
20:62218490:CCGC:C	donor_gain	1.0000
20:62218490:CCGCT:C	donor_gain	1.0000
20:62219717:TTACC:T	donor_loss	1.0000
20:62219718:TACC:T	donor_loss	1.0000
20:62219719:ACC:A	donor_loss	1.0000
20:62219720:CCGA:C	donor_gain	1.0000
20:62216927:C:CC	acceptor_gain	0.9900
20:62217808:C:CT	acceptor_gain	0.9900
20:62217809:A:T	acceptor_gain	0.9900
20:62218484:GACTC:G	donor_loss	0.9900
20:62218485:ACTC:A	donor_loss	0.9900
20:62218521:G:C	donor_gain	0.9900
20:62218626:G:C	acceptor_gain	0.9900
20:62218635:A:C	acceptor_gain	0.9900
20:62219716:TTTA:T	donor_loss	0.9900
20:62219719:A:AC	donor_gain	0.9900
20:62219720:C:CC	donor_gain	0.9900
20:62219723:A:AC	donor_gain	0.9900

AlphaMissense

2834 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:62216705:G:C	S213R	0.999
20:62216705:G:T	S213R	0.999
20:62216707:T:G	S213R	0.999
20:62219815:G:C	N52K	0.999
20:62219815:G:T	N52K	0.999
20:62218521:G:C	S129R	0.998
20:62218521:G:T	S129R	0.998
20:62218523:T:G	S129R	0.998
20:62219721:C:G	G84R	0.998
20:62219746:G:C	N75K	0.998
20:62219746:G:T	N75K	0.998
20:62219820:C:G	G51R	0.998
20:62216087:G:C	F419L	0.997
20:62216087:G:T	F419L	0.997
20:62216089:A:G	F419L	0.997
20:62218608:C:A	W100C	0.997
20:62218608:C:G	W100C	0.997
20:62218610:A:G	W100R	0.997
20:62218610:A:T	W100R	0.997
20:62218657:C:T	G84D	0.997
20:62219794:G:C	F59L	0.997
20:62219794:G:T	F59L	0.997
20:62219796:A:G	F59L	0.997
20:62216120:G:C	N408K	0.996
20:62216120:G:T	N408K	0.996
20:62216715:G:T	P210H	0.996
20:62216723:G:C	F207L	0.996
20:62216723:G:T	F207L	0.996
20:62216725:A:G	F207L	0.996
20:62216781:C:G	C188S	0.996

dbSNP variants (sampled 300 via entrez): RS1000467386 (20:62220705 T>G), RS1000735503 (20:62220964 G>A), RS1000839224 (20:62220551 G>A), RS1001202932 (20:62214926 G>A,T), RS1001209005 (20:62222012 G>A), RS1001554313 (20:62220307 G>A), RS1001586886 (20:62220498 G>A), RS1001891544 (20:62221408 G>A), RS1001924129 (20:62221569 G>T), RS1002763640 (20:62221682 G>A), RS1003358178 (20:62219700 G>A), RS1003837620 (20:62219399 C>A,G), RS1003846385 (20:62218324 G>A), RS1004323713 (20:62221132 G>A), RS1004801512 (20:62220117 GCGGGGCCGGGGC>G,GCGGGGC,GCGGGGCCGGGGCCGGGGC)

Disease associations

OMIM: gene MIM:604525 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001942_4	Prostate cancer	4.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111378 (SELECTIVITY GROUP), CHEMBL264 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

172 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 192,035 (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
CHEMBL1085	ACETOPHENAZINE	4	5,134
CHEMBL1088	MESORIDAZINE	4	12,814
CHEMBL1094636	NIRAPARIB	4	6,433
CHEMBL1101	BIPERIDEN	4	11,044
CHEMBL1112	ARIPIPRAZOLE	4	24,205
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1179047	CHLOROPROCAINE	4	52,577
CHEMBL1190	DECAMETHONIUM	4	1,139
CHEMBL1196	PROPARACAINE	4	12,973
CHEMBL1198	PRAMOXINE	4	10,295
CHEMBL1200	BENOXINATE	4	6,712
CHEMBL1201196	SERTACONAZOLE	4	9,003
CHEMBL1201217	DYCLONINE	4	7,785
CHEMBL1201219	VECURONIUM	4	26
CHEMBL1201287	DEXBROMPHENIRAMINE	4	3,796
CHEMBL1201303	PYRVINIUM	4	1,797
CHEMBL1201304	INDOCYANINE GREEN ACID FORM	4	7,044
CHEMBL1201342	METHIXENE	4	1,320
CHEMBL1201346	BALSALAZIDE	4	8,319
CHEMBL1201349	HEXAFLUORENIUM	4	664
CHEMBL1201353	DEXCHLORPHENIRAMINE	4
CHEMBL1206	ETHOPROPAZINE	4
CHEMBL1231	OXYBUTYNIN	4
CHEMBL12610	BENZYDAMINE	4
CHEMBL1262	OXICONAZOLE	4
CHEMBL126224	IPRINDOLE	4
CHEMBL1287853	FEDRATINIB	4
CHEMBL1372950	NICERGOLINE	4
CHEMBL1378	THIETHYLPERAZINE	4
CHEMBL1401	NITAZOXANIDE	4

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3787429	Efficacy	3	risperidone	Schizophrenia
rs3787430	Efficacy	3	risperidone	Schizophrenia

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3787429	HRH3	3	0.25	1	risperidone
rs3787430	HRH3	3	2.50	1	risperidone

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Histamine receptors

Most potent curated ligand interactions (62 total), top 25:

Ligand	Action	Affinity	Parameter
[123I]iodoproxyfan	Antagonist	10.2	pKd
iodoproxyfan	Full agonist	10.0	pKi
GSK334429	Antagonist	9.89	pKi
imetit	Full agonist	9.7	pKi
immepip	Full agonist	9.7	pKi
GSK-189254	Inverse agonist	9.7	pKi
clobenpropit	Antagonist	9.41	pKi
A-349821	Inverse agonist	9.4	pKi
ABT-239	Inverse agonist	9.4	pKi
VUF26063	Antagonist	9.3	pKi
N-methylhistamine	Full agonist	9.3	pKi
(R)-α-methylhistamine	Full agonist	9.2	pKi
[3H](R)-α-methylhistamine	Full agonist	9.2	pKd
JNJ-5207852	Antagonist	9.2	pKi
[125I]iodophenpropit	Antagonist	9.2	pKd
N-[3H]methylhistamine	Full agonist	9.1	pKd
immethridine	Full agonist	9.1	pKi
N-α-methylhistamine	Full agonist	9.0	pKi
N-[3H]α-methylhistamine	Full agonist	9.0	pKd
methimepip	Full agonist	9.0	pKi
enerisant	Inverse agonist	8.78	pKi
MK-0249	Inverse agonist	8.77	pKi
FUB 349	Antagonist	8.7	pKi
iodophenpropit	Antagonist	8.7	pKi
PF-03654746	Antagonist	8.64	pKi

Binding affinities (BindingDB)

263 measured of 373 human assays (385 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[1-(6-methoxycarbonyl-3-pyridinyl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.1 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-(6-methoxycarbonyl-3-pyridinyl)piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	0.2 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-[6-(hydroxymethyl)-3-pyridinyl]piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.2 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-[6-(methoxymethyl)-3-pyridinyl]piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.2 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
(2R)-N,3-dimethyl-2-(methylamino)-N-[(1R,2S,5S,6S,9R,12S,13R,16S)-6,7,13-trimethyl-7-azapentacyclo[10.8.0.0^{2,9}.0^{5,9}.0^{13,18}]icos-18-en-16-yl]butanamide	KI	0.21 nM
(2S,3S)-2-amino-N,3-dimethyl-N-[(1R,2S,5S,6S,9R,12S,13R,16S)-6,7,13-trimethyl-7-azapentacyclo[10.8.0.0^{2,9}.0^{5,9}.0^{13,18}]icos-18-en-16-yl]pentanamide	KI	0.22 nM
[1-(5-methoxy-2-pyridinyl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.3 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-[6-(methoxymethyl)-3-pyridinyl]piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	0.3 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-(1,3-thiazol-5-yl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.3 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
2-(3H-imidazol-4-yl)ethylsulfanylmethanimidamide	KI	0.3 nM
(2R,3R)-2-amino-N,3-dimethyl-N-[(1R,2S,5S,6S,9R,12S,13R,16S)-6,7,13-trimethyl-7-azapentacyclo[10.8.0.0^{2,9}.0^{5,9}.0^{13,18}]icos-18-en-16-yl]pentanamide	KI	0.37 nM
(1-pyridin-2-ylpiperidin-4-yl) 4-cyclobutylpiperazine-1-carboxylate	KI	0.4 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-(5-fluoro-2-pyridinyl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.4 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-(6-isocyano-2-pyridinyl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.4 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-(6-methoxycarbonyl-2-pyridinyl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.4 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-[6-(hydroxymethyl)-3-pyridinyl]piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	0.4 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
(1-pyridin-4-ylpiperidin-4-yl) 4-cyclobutylpiperazine-1-carboxylate	KI	0.4 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
(1-imidazo[1,2-a]pyridin-7-ylpiperidin-4-yl) 4-cyclobutylpiperazine-1-carboxylate	KI	0.4 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-(2-methylimidazo[1,2-a]pyridin-7-yl)piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	0.4 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
4-(1H-imidazol-4-ylmethyl)piperidine	KI	0.4 nM
[1-(2-oxopiperidin-4-yl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.5 nM	US-9034874: Carbamate/urea derivatives
[1-(5-methoxy-2-pyridinyl)piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	0.5 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-(6-methoxy-2-pyridinyl)piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	0.5 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-(6-methoxypyrazin-2-yl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.5 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
N(alpha)-Methylhistamine	KI	0.5 nM
[1-(6-carbamoyl-3-pyridinyl)piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	0.6 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
5-{3-[(4-iodophenyl)methoxy]propyl}-1H-imidazole	KI	0.63 nM
ethyl 2-[[4-[4-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]phenyl]phenyl]methoxy]acetate	IC50	0.67 nM	US-9365511: Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders
[1-[5-(2-oxopyrrolidin-1-yl)-2-pyridinyl]piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.7 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-[6-(methoxymethyl)-2-pyridinyl]piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	0.7 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-(6-isocyano-2-pyridinyl)piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	0.7 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
5-[[4-[4-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]phenyl]phenyl]methyl]-2H-tetrazole	IC50	0.78 nM	US-9365511: Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders
(2S)-2-[3-[4-[4-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]phenyl]phenyl]propanoylamino]propanoic acid	IC50	0.79 nM	US-9365511: Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders
4-(1H-imidazol-5-ylmethyl)pyridine	KI	0.794 nM
3-[2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl]benzonitrile	IC50	0.834 nM	US-9029381: Cyclopropyl amide derivatives
N-[[2-(4-cyclopropylpiperazin-1-yl)-1,3-benzothiazol-6-yl]methyl]cyclopropanamine	KI	0.9 nM	US-8772285: Benzothiazoles having histamine H3 receptor activity
[1-(2-oxopiperidin-4-yl)piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	0.9 nM	US-9034874: Carbamate/urea derivatives
[1-[5-(1,3-thiazol-2-yl)-2-pyridinyl]piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	0.9 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
1-[2-[4-[4-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]phenyl]phenyl]ethyl]tetrazole	IC50	0.93 nM	US-9365511: Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders
tert-butyl 2-methyl-2-[3-[4-[4-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]phenyl]phenyl]propanoylamino]propanoate	IC50	0.95 nM	US-9365511: Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders
ethyl 1-[3-[4-[4-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]phenyl]phenyl]propanoyl]piperidine-4-carboxylate	IC50	0.96 nM	US-9365511: Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders
4-[4-[4-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]phenyl]phenyl]butanoic acid	IC50	0.97 nM	US-9365511: Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders
methyl 2-[3-[4-[4-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]phenyl]phenyl]propanoylamino]acetate	IC50	0.99 nM	US-9365511: Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders
[1-[6-(trifluoromethyl)-2-pyridinyl]piperidin-4-yl] 4-propan-2-ylpiperazine-1-carboxylate	KI	1 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
2-[3-(1H-imidazol-4-ylmethyl)phenyl]-4,4,6-trimethyl-5,6-dihydro-4H-1,3-oxazine	KI	1 nM
4-(1H-imidazol-5-ylmethyl)-1-methylpiperidine	KI	1 nM
[1-(1-methyl-6-oxopyridazin-3-yl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	1.1 nM	US-9034874: Carbamate/urea derivatives
[1-[3-(trifluoromethyl)-2-pyridinyl]piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	1.1 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
(1-pyridin-4-ylpiperidin-4-yl) 4-propan-2-ylpiperazine-1-carboxylate	KI	1.1 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors
[1-(6-methoxypyridazin-3-yl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate	KI	1.1 nM	US-9216182: Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.72	Kd	0.01905	nM	CHEMBL272077
10.70	Kd	0.01995	nM	CHEMBL401683
10.65	Kd	0.02239	nM	CHEMBL258349
10.60	Ki	0.02512	nM	CHEMBL3094128
10.52	Ki	0.03	nM	CHEMBL3753475
10.51	Ki	0.03125	nM	CHEMBL508712
10.44	Kd	0.03631	nM	CHEMBL257208
10.40	Kd	0.03981	nM	CHEMBL272699
10.40	EC50	0.03981	nM	IMMEPIP
10.38	Ki	0.042	nM	CHEMBL455288
10.37	Kd	0.04266	nM	CHEMBL257009
10.37	Kd	0.04266	nM	CHEMBL273136
10.35	Ki	0.045	nM	CHEMBL2413837
10.32	Kd	0.04786	nM	CHEMBL272698
10.32	Kd	0.04786	nM	CHEMBL272917
10.30	Ki	0.05	nM	CHEMBL197747
10.30	Kd	0.05012	nM	CHEMBL404572
10.30	Ki	0.05	nM	CHEMBL1085337
10.30	EC50	0.05012	nM	IODOPROXYFAN
10.24	Ki	0.057	nM	CHEMBL2413835
10.22	Ki	0.06026	nM	JNJ-5207852
10.20	Ki	0.0625	nM	CHEMBL453893
10.17	Ki	0.068	nM	CHEMBL470609
10.16	EC50	0.06918	nM	CHEMBL1490875
10.16	Ki	0.06875	nM	CHEMBL488249
10.11	Ki	0.07812	nM	CHEMBL454642
10.10	Ki	0.07943	nM	CHEMBL14364
10.10	Ki	0.07943	nM	CHEMBL3092823
10.10	Ki	0.08	nM	CHEMBL178853
10.10	Ki	0.08	nM	CHEMBL199245
10.10	EC50	0.08	nM	CHEMBL1490875
10.10	Kd	0.07943	nM	CHEMBL257909
10.09	Kd	0.08128	nM	CHEMBL573817
10.08	Ki	0.08318	nM	CHEMBL178853
10.07	Ki	0.086	nM	CHEMBL14364
10.07	Ki	0.08511	nM	CHEMBL178682
10.05	Ki	0.09	nM	CHEMBL178682
10.04	Ki	0.091	nM	CHEMBL15153
10.03	Ki	0.09333	nM	CHEMBL513193
10.03	Ki	0.094	nM	CHEMBL513193
10.03	Ki	0.09375	nM	CHEMBL507360
10.03	Ki	0.09375	nM	CHEMBL454879
10.03	Ki	0.09375	nM	CHEMBL453654
10.01	Ki	0.09688	nM	CHEMBL487059
10.00	Ki	0.1	nM	CHEMBL15153
10.00	IC50	0.1	nM	CHEMBL2387288
10.00	IC50	0.1	nM	CHEMBL2387314
10.00	Ki	0.1	nM	CHEMBL2413824
10.00	Kd	0.1	nM	CLOBENPROPIT
10.00	Ki	0.1	nM	CHEMBL3087669

PubChem BioAssay actives

3713 with measured affinity, of 6100 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
1-[3-[4-[2-(piperidin-1-ylmethyl)phenyl]phenoxy]propyl]piperidine	763544: Displacement of [125I]iodoproxyfan from histamine H3 receptor (unknown origin) expressed in CHO cells	ki	<0.0001	uM
2-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-3,8-dimethylquinazolin-4-one	616658: Displacement of [125I]Iodoproxyfan from human recombinant histamine H3 receptor by Competitive binding assay	ki	<0.0001	uM
2-(1-cyclobutylpiperidin-4-yl)-6-(1-cyclobutylpiperidin-4-yl)oxy-3,4-dihydroisoquinolin-1-one	1272284: Binding affinity to recombinant human H3 receptor	ki	<0.0001	uM
(4-cyclopropyl-1,4-diazepan-1-yl)-[3-(methylaminomethyl)-4-phenoxyphenyl]methanone	315152: Antagonist activity at human histamine H3 receptor	kd	<0.0001	uM
[4-(3-chloro-4-fluorophenoxy)-3-(methylaminomethyl)phenyl]-(4-cyclopropyl-1,4-diazepan-1-yl)methanone	315152: Antagonist activity at human histamine H3 receptor	kd	<0.0001	uM
[4-(4-chloro-2-fluorophenoxy)-3-(methylaminomethyl)phenyl]-(4-cyclopropyl-1,4-diazepan-1-yl)methanone	315152: Antagonist activity at human histamine H3 receptor	kd	<0.0001	uM
3-[4-(4-cyclopropyl-1,4-diazepane-1-carbonyl)-2-(methylaminomethyl)phenoxy]benzonitrile	315152: Antagonist activity at human histamine H3 receptor	kd	<0.0001	uM
(4-cyclopropyl-1,4-diazepan-1-yl)-[4-(4-fluorophenoxy)-3-(methylaminomethyl)phenyl]methanone	315152: Antagonist activity at human histamine H3 receptor	kd	<0.0001	uM
(4-cyclopropyl-1,4-diazepan-1-yl)-[4-(3-methoxyphenoxy)-3-(methylaminomethyl)phenyl]methanone	315152: Antagonist activity at human histamine H3 receptor	kd	<0.0001	uM
2-[4-(4-cyclopropyl-1,4-diazepane-1-carbonyl)-2-(methylaminomethyl)phenoxy]benzonitrile	315152: Antagonist activity at human histamine H3 receptor	kd	<0.0001	uM
2-[4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]piperazin-1-yl]ethyl 4-(3-piperidin-1-ylpropoxy)benzoate	392463: Displacement of [125I]iodoproxyfan from human histamine H3 receptor expressed in CHO/HEK293 cells	ki	<0.0001	uM
4-(1H-imidazol-5-ylmethyl)piperidine	548991: Agonist activity at human histamine H3 receptor expressed in human SK-N-MC cells by CRE-beta galactosidase reporter gene assay	ec50	<0.0001	uM
N-[4-(3-piperidin-1-ylpropoxy)phenyl]quinolin-4-amine	86480: Activity at Histamine H3 receptor expressed in CHO cells using [125I]iodoproxyfan binding assay	ki	0.0001	uM
1-[[4-(4-piperidin-1-ylbut-1-ynyl)phenyl]methyl]piperidine	436630: Antagonist activity at human histamine H3 receptor expressed in SK-N-MC cells assessed as inhibition of forskolin-stimulated cAMP accumulation treated 10 min before histamine challenge	kd	0.0001	uM
1-[[3-(4-piperidin-1-ylbut-1-ynyl)phenyl]methyl]piperidine	436630: Antagonist activity at human histamine H3 receptor expressed in SK-N-MC cells assessed as inhibition of forskolin-stimulated cAMP accumulation treated 10 min before histamine challenge	kd	0.0001	uM
1-[6-[(3-cyclobutyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]-3-pyridinyl]azetidin-2-one	1059553: Antagonist activity at human histamine H3 receptor expressed in CHOK1 cells assessed as inhibition of GTPgammaS binding	ki	0.0001	uM
7-chloro-N-[4-(3-piperidin-1-ylpropoxy)phenyl]quinolin-4-amine	86480: Activity at Histamine H3 receptor expressed in CHO cells using [125I]iodoproxyfan binding assay	ki	0.0001	uM
(4-propan-2-yl-1,4-diazepan-1-yl)-[1-[6-(trifluoromethyl)-3-pyridinyl]piperidin-4-yl]methanone	1163942: Displacement of [3H]N-alpha-Methylhistamine from human recombinant H3 receptor expressed in HEK293 cells by competitive binding assay	ki	0.0001	uM
2-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-8-fluoro-3-methylquinazolin-4-one	616658: Displacement of [125I]Iodoproxyfan from human recombinant histamine H3 receptor by Competitive binding assay	ki	0.0001	uM
2-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-6-methoxy-3-methylquinazolin-4-one	616658: Displacement of [125I]Iodoproxyfan from human recombinant histamine H3 receptor by Competitive binding assay	ki	0.0001	uM
6-methyl-5-[6-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]quinolin-2-yl]-[1,3]thiazolo[3,2-b][1,2,4]triazole	483429: Displacement of [3H]N-alpha-methylhistamine from human cloned histamine H3 receptor	ki	0.0001	uM
4-[[2-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]-1-benzofuran-5-yl]methylamino]pyridine-2,6-dicarbonitrile	254441: In vitro binding affinity for human histamine H3 receptor using [3H]N-alpha-methylhistamine	ki	0.0001	uM
1-[6-[(3-cyclopentyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]-3-pyridinyl]pyrrolidin-2-one	1059553: Antagonist activity at human histamine H3 receptor expressed in CHOK1 cells assessed as inhibition of GTPgammaS binding	ki	0.0001	uM
1-[4-[6-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]quinolin-2-yl]phenyl]pyridin-4-one	483429: Displacement of [3H]N-alpha-methylhistamine from human cloned histamine H3 receptor	ki	0.0001	uM
5-fluoro-1-[4-(3-piperidin-1-ylpropoxy)phenyl]-2-pyridin-2-ylbenzimidazole	348435: Antagonist activity at human histamine H3 receptor expressed in HEK293 cells assessed as reversal of N-alpha-methylhistamine-induced inhibition of forskolin-stimulated cAMP formation	ki	0.0001	uM
2-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-8-methoxy-3-methylpyrido[3,4-d]pyrimidin-4-one	616658: Displacement of [125I]Iodoproxyfan from human recombinant histamine H3 receptor by Competitive binding assay	ki	0.0001	uM
2-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-7-methoxy-3-methylquinazolin-4-one	616658: Displacement of [125I]Iodoproxyfan from human recombinant histamine H3 receptor by Competitive binding assay	ki	0.0001	uM
5-methyl-4-[6-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]quinolin-2-yl]-3-phenyl-1,2-oxazole	483429: Displacement of [3H]N-alpha-methylhistamine from human cloned histamine H3 receptor	ki	0.0001	uM
N-[2-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]-1-benzofuran-5-yl]-3-nitropyridin-2-amine	254441: In vitro binding affinity for human histamine H3 receptor using [3H]N-alpha-methylhistamine	ki	0.0001	uM
2-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-3-methylquinazolin-4-one	616658: Displacement of [125I]Iodoproxyfan from human recombinant histamine H3 receptor by Competitive binding assay	ki	0.0001	uM
8-chloro-2-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-3-methylquinazolin-4-one	616658: Displacement of [125I]Iodoproxyfan from human recombinant histamine H3 receptor by Competitive binding assay	ki	0.0001	uM
3-benzyl-2-[4-(3-piperidin-1-ylpropoxy)phenyl]quinazolin-4-one	616658: Displacement of [125I]Iodoproxyfan from human recombinant histamine H3 receptor by Competitive binding assay	ki	0.0001	uM
6-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]-2-pyridin-3-ylquinoline	483429: Displacement of [3H]N-alpha-methylhistamine from human cloned histamine H3 receptor	ki	0.0001	uM
N-[2-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]-1-benzofuran-5-yl]pyrazin-2-amine	254441: In vitro binding affinity for human histamine H3 receptor using [3H]N-alpha-methylhistamine	ki	0.0001	uM
N-[2-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]-1-benzofuran-5-yl]pyrimidin-5-amine	254441: In vitro binding affinity for human histamine H3 receptor using [3H]N-alpha-methylhistamine	ki	0.0001	uM
2-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]quinoline	483429: Displacement of [3H]N-alpha-methylhistamine from human cloned histamine H3 receptor	ki	0.0001	uM
1-[6-[(3-cyclobutyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]-3-pyridinyl]-3-methylimidazolidin-2-one	1059553: Antagonist activity at human histamine H3 receptor expressed in CHOK1 cells assessed as inhibition of GTPgammaS binding	ki	0.0001	uM
N-[2-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]-1-benzofuran-5-yl]-5-nitropyridin-2-amine	254441: In vitro binding affinity for human histamine H3 receptor using [3H]N-alpha-methylhistamine	ki	0.0001	uM
1-[3-[4-[4-(3-piperidin-1-ylpropoxy)phenyl]phenoxy]propyl]piperidine	763544: Displacement of [125I]iodoproxyfan from histamine H3 receptor (unknown origin) expressed in CHO cells	ki	0.0001	uM
2-(1H-imidazol-5-yl)ethyl carbamimidothioate;dihydrobromide	1359179: Agonist activity at human H3R expressed in HEK293 cells harboring glosensor-22F cAMP plasmid DNA assessed as inhibition of forskolin-stimulated cAMP accumulation preincubated with cells followed by forskolin addition measured after 10 mins by luminescence assay	ec50	0.0001	uM
6-(1-propan-2-ylpiperidin-4-yl)oxy-2-(1-propan-2-ylpyrrolidin-3-yl)-3,4-dihydroisoquinolin-1-one	1272284: Binding affinity to recombinant human H3 receptor	ki	0.0001	uM
5-[3-[(4-iodophenyl)methoxy]propyl]-1H-imidazole	548991: Agonist activity at human histamine H3 receptor expressed in human SK-N-MC cells by CRE-beta galactosidase reporter gene assay	ec50	0.0001	uM
(3Z)-3-benzylidene-N-cyclohexyl-1-(4-methoxyphenyl)-4-oxo-2-(3,4,5-trifluorophenyl)azetidine-2-carboxamide	1359179: Agonist activity at human H3R expressed in HEK293 cells harboring glosensor-22F cAMP plasmid DNA assessed as inhibition of forskolin-stimulated cAMP accumulation preincubated with cells followed by forskolin addition measured after 10 mins by luminescence assay	ec50	0.0001	uM
(3Z)-3-benzylidene-N-tert-butyl-4-oxo-2-phenyl-1-(3,4,5-trimethoxyphenyl)azetidine-2-carboxamide	1359179: Agonist activity at human H3R expressed in HEK293 cells harboring glosensor-22F cAMP plasmid DNA assessed as inhibition of forskolin-stimulated cAMP accumulation preincubated with cells followed by forskolin addition measured after 10 mins by luminescence assay	ec50	0.0001	uM
1-[3-[[(8R,9S,13S,14S,17S)-13-methyl-17-pyrrolidin-1-yl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl]oxy]propyl]pyrrolidine	1959096: Inverse agonist activity at recombinant human histamine H3 receptor expressed in CHO-K1 cells preincubated for 10 mins followed by [35S]GTPgammaS addition and measured after 60 mins by TopCount NXT based scintillation analysis	ec50	0.0001	uM
1-[3-[4-[4-[(Z)-3-piperidin-1-ylprop-1-enyl]phenyl]phenoxy]propyl]piperidine	763544: Displacement of [125I]iodoproxyfan from histamine H3 receptor (unknown origin) expressed in CHO cells	ki	0.0001	uM
(4-cyclopropyl-1,4-diazepan-1-yl)-[4-(3-fluorophenoxy)-3-(methylaminomethyl)phenyl]methanone	315152: Antagonist activity at human histamine H3 receptor	kd	0.0001	uM
(4-cyclopropyl-1,4-diazepan-1-yl)-[3-(methylaminomethyl)-4-(3-methyl-4-methylsulfanylphenoxy)phenyl]methanone	315152: Antagonist activity at human histamine H3 receptor	kd	0.0001	uM
4-[4-(4-cyclopropyl-1,4-diazepane-1-carbonyl)-2-(methylaminomethyl)phenoxy]benzonitrile	315152: Antagonist activity at human histamine H3 receptor	kd	0.0001	uM
[3-(methylaminomethyl)-4-(4-methylsulfanylphenoxy)phenyl]-(4-propan-2-yl-1,4-diazepan-1-yl)methanone	315152: Antagonist activity at human histamine H3 receptor	kd	0.0001	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
alpha-methylhistamine	affects binding, decreases reaction, increases reaction, increases activity	3
mercuric bromide	increases expression, affects cotreatment	2
imetit	affects binding, increases activity	2
clobenpropit	affects binding, decreases activity	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
ethyl-p-hydroxybenzoate	decreases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
N-methylaminoethanol	affects binding, decreases activity	1
pyrrolidine	decreases activity, affects binding	1
diethylamine	affects binding, decreases activity	1
dimethylamine	affects binding, decreases activity	1
N-methylhistamine	affects binding, decreases reaction	1
thioperamide	decreases activity, affects binding	1
proxyfan	affects binding, increases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
5-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-2-pyrazinecarboxamide	affects binding, decreases activity	1
1-(1-methylethyl)-4-((1-(6-(trifluoromethyl)-3-pyridinyl)-4-piperidinyl)carbonyl)hexahydro-1H-1,4-diazepine	affects binding, decreases activity	1
2-methylpyrrolidine	affects binding, decreases activity	1
6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one	increases reaction, affects binding, decreases reaction	1
N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidinylmethyl)phenyl)cyclobutanecarboxamide	affects binding, decreases reaction	1
3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-N-(2-methylpropyl)cyclobutanecarboxamide	affects binding, decreases reaction	1
Benzene	affects binding, decreases activity	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Furans	affects binding, decreases activity	1
Guanosine Triphosphate	affects binding, decreases reaction, increases reaction	1
Histamine	affects binding, increases activity	1
Methylhistamines	affects binding, increases activity	1
Tetrachlorodibenzodioxin	decreases expression	1

ChEMBL screening assays

886 unique, capped per target: 650 binding, 232 functional, 4 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
CHEMBL4406568	ADMET	Antagonist activity at human ARMS2-PK2-tagged Gi/Go-coupled H3 receptor expressed in CHOK1 cells assessed as inhibition of (R)(-)-alpha-methylhistamine dihydrochloride-induced beta-arrestin recruitment at 10 uM measured after 120 mins by be	Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_H449	CHO-K1/H3/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KV37	cAMP Hunter CHO-K1 HRH3 Gi	Spontaneously immortalized cell line	Female
CVCL_KX85	PathHunter CHO-K1 HRH3 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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