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P2RX4

gene
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Also known as P2X4

Summary

P2RX4 (purinergic receptor P2X 4, HGNC:8535) is a protein-coding gene on chromosome 12q24.31, encoding P2X purinoceptor 4 (Q99571). ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and calcium.

The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel with high calcium permeability. The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists suramin and PPADS. The product of this gene has the lowest sensitivity for these antagonists. Multiple alternatively spliced transcript variants, some protein-coding and some not protein-coding, have been found for this gene.

Source: NCBI Gene 5025 — RefSeq curated summary.

At a glance

  • GWAS associations: 2
  • Clinical variants (ClinVar): 77 total
  • Druggable target: yes — 5 molecules with ChEMBL bioactivity
  • MANE Select transcript: NM_002560

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:8535
Approved symbolP2RX4
Namepurinergic receptor P2X 4
Location12q24.31
Locus typegene with protein product
StatusApproved
AliasesP2X4
Ensembl geneENSG00000135124
Ensembl biotypeprotein_coding
OMIM600846
Entrez5025

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 15 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000314442, ENST00000337233, ENST00000359949, ENST00000397924, ENST00000499638, ENST00000538417, ENST00000538701, ENST00000540930, ENST00000541187, ENST00000542067, ENST00000543318, ENST00000543430, ENST00000543984, ENST00000887509, ENST00000887510, ENST00000887511, ENST00000887512, ENST00000887513, ENST00000887514, ENST00000887515, ENST00000917535, ENST00000917536, ENST00000966496, ENST00000966497

RefSeq mRNA: 4 — MANE Select: NM_002560 NM_001256796, NM_001261397, NM_001261398, NM_002560

CCDS: CCDS58282, CCDS9214

Canonical transcript exons

ENST00000337233 — 12 exons

ExonStartEnd
ENSE00003479031121232997121233092
ENSE00003502562121232414121232507
ENSE00003537787121210129121210298
ENSE00003585161121228725121228866
ENSE00003608177121233523121234106
ENSE00003633867121217134121217281
ENSE00003636294121222094121222166
ENSE00003643168121222947121223043
ENSE00003667381121228533121228613
ENSE00003667930121228963121229099
ENSE00003677353121232611121232676
ENSE00003754335121221913121221984

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 95.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.8612 / max 140.2853, expressed in 1740 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter IDTPM avgSamples expressed
12840711.45841726
1284150.7245265
1284080.2570132
1284100.162552
1284090.160569
1284110.098336

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
mucosa of transverse colonUBERON:000499195.31gold quality
cerebellar hemisphereUBERON:000224593.90gold quality
right hemisphere of cerebellumUBERON:001489093.84gold quality
cerebellar cortexUBERON:000212993.82gold quality
granulocyteCL:000009493.30gold quality
body of pancreasUBERON:000115093.09gold quality
ileal mucosaUBERON:000033192.77gold quality
monocyteCL:000057692.76gold quality
mononuclear cellCL:000084292.50gold quality
cerebellumUBERON:000203792.32gold quality
leukocyteCL:000073892.26gold quality
transverse colonUBERON:000115792.16gold quality
colonic mucosaUBERON:000031791.58gold quality
rectumUBERON:000105291.12gold quality
stromal cell of endometriumCL:000225590.82gold quality
pancreasUBERON:000126490.67gold quality
mucosa of sigmoid colonUBERON:000499390.38gold quality
small intestine Peyer’s patchUBERON:000345490.10gold quality
placentaUBERON:000198789.87gold quality
jejunal mucosaUBERON:000039989.77gold quality
body of stomachUBERON:000116189.56gold quality
islet of LangerhansUBERON:000000689.31gold quality
duodenumUBERON:000211489.26gold quality
small intestineUBERON:000210889.11gold quality
intestineUBERON:000016088.79gold quality
large intestineUBERON:000005988.77gold quality
minor salivary glandUBERON:000183088.72gold quality
colonUBERON:000115588.66gold quality
gall bladderUBERON:000211088.41gold quality
upper lobe of left lungUBERON:000895288.40gold quality

Single-cell (SCXA)

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

ExperimentMarker?Max mean expression
E-ANND-3yes15.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

Literature-anchored findings (GeneRIF, showing 40)

  • Results show that P2X4 and P2X6 receptors are associated with VE-cadherin at HUVEC adherens junctions. (PMID:12088286)
  • shear stress stimulates pulmonary artery endothelial cells to release ATP, which activates Ca2+ influx via P2X4 receptors. (PMID:12714321)
  • We have identified a distinct subpopulation of P2X4-positive macrophages infiltrating the dystrophic fibres. These cells were absent from normal muscle and rarely present in the dystrophic muscle taken before and after the onset of degeneration. (PMID:15006691)
  • Increased contractility likely underlies survival benefit from P2X4 receptor overexpression. (PMID:15130891)
  • in human parotid acinar cells, in addition to modulation of Ca(2+) release, Ca(2+) influx through P2X(4)R may constitute a further locus for the synergistic effects of Ca(2+) and PKA activation. (PMID:15262999)
  • wild-type desensitization properties requires an aromatic moiety at position 374 and an amino rather than a guanidino group at position 373 (PMID:16533808)
  • P2X4 receptor-specific residues contribute to the ivermectin effects on channel deactivation (PMID:16949036)
  • Main role for P2X(4) receptor in nucleotide-induced apoptosis in human mesangial cells, indicating a relevant role for purinergic signaling in regulating death rate in these cells. (PMID:17264311)
  • This review discusses the need to reinterpret the assumed “go-it alone” function of the P2X7 receptor in light of convincing biochemical and electrophysiological evidence for the existence of P2X4/P2X7 heteromeric receptors. (PMID:17895406)
  • support a common site of ATP action at P2X receptors and suggest that non-conserved residues also play a regulatory role in agonist action (PMID:18487206)
  • analysis of molecular shape, architecture, and size of P2X4 receptors (PMID:18635539)
  • INF-gamma selectively increases P2X4-receptor gene expression, leading to an up-regulation of purinergic signaling in vascular endothelial cells. (PMID:18678988)
  • P2X(4) and P2X(7) receptors are expressed by human osteoblast-like cells. P2X(7) receptor is mainly responsible for pore formation although P2X(4) receptors may also be involved. (PMID:19226284)
  • This study presents a picture whereby P2X(4)R become functional in response to initial phagocytic stimuli but return to a non-functional state during sustained activation by classical macrophage activation. (PMID:19283779)
  • Data confirmed the presence of functional P2X1, P2X4 and P2X7 receptors in LAD2 cells and HLMCs. (PMID:19552691)
  • Results suggest that amyloid beta(1-42)-induced synaptic dysfunction and neuronal death may involve perturbations in P2X4 purinergic receptors. (PMID:19562525)
  • These data have identified the first transcription factor involved in P2X receptor expression. (PMID:19953327)
  • T-cell receptor stimulation results in the translocation of P2X1 and P2X4 receptors and pannexin-1 hemichannels to the immune synapse. (PMID:20660288)
  • Lipid raft association and cholesterol sensitivity of P2X1-4 receptors for ATP (PMID:20699225)
  • we have identified an extracellular signaling pathway where Tbeta4 increases cell surface ATP levels via ATP synthase and have shown further that ATP-responsive P2X4 receptor is required for Tbeta4-induced cell migration (PMID:21106936)
  • Studies indicate that P2X1, P2X2, and P2X4 receptors are detected in preglomerular microvessels. (PMID:21768526)
  • Owing to their favorable diameters and equivalent spacing, the lateral portals split the task of ion supply threefold and minimize an ion’s diffusive path before it succumbs to transmembrane electrochemical gradients (PMID:21808018)
  • Transcripts of five different isoforms of P2X4 receptors are expressed in human liver cells indicating that they represent an important component of the purinergic signaling complex in HCV induced liver pathogenesis. (PMID:21899776)
  • The Tyr315>Cys mutation (rs28360472) reduced the peak amplitude of the ATP-induced inward current. In Victorian Family Heart Study participants, 1 minor allele increased pulse pressure by 2.84 mm Hg. (PMID:22068874)
  • Allosteric modulation of Ca2+ flux in ligand-gated cation channel (P2X4) by actions on lateral portals (PMID:22219189)
  • The present article highlights the recent advances in our understanding of microglia-neuron interactions in neuropathic pain by focusing on the signaling and regulation of the P2X4R–{REVIEW} (PMID:22528681)
  • found that pharmacological inhibition of P2X4 receptors with TNP-ATP inhibited transcriptional up-regulation of TNF-alpha and IFN-gamma in gammadelta T cells stimulated with anti-CD3/CD28-coated beads (PMID:22753954)
  • Neuropathic pain may be driven by P2X4R+ microglia. (PMID:22837036)
  • We demonstrate here that stimulation with ADP or ATP induces significant reversible inhibition of C. trachomatis development in cervical epithelial cells through stimulation of the purinergic receptor P2X4. (PMID:22988022)
  • IL-18 associates to microvesicles shed from human macrophages by a LPS/TLR-4 independent mechanism in response to P2X receptor stimulation. (PMID:22996386)
  • These findings highlight Rab5 GTPase as a key regulator of P2X4 receptor cell surface expression and internalisation (PMID:23086000)
  • This is the first study demonstrating an association of non-synonymous polymorphisms in the P2RX ( 4 ) and the risk of osteoporosis, suggesting a role of the P2X ( 4 ) R in the regulation of bone mass (PMID:23138503)
  • results demonstrate that a haplotype including two rare variants in P2RX7 and P2RX4 confers a functional interaction between these two variant receptors that impairs the normal scavenger function of macrophages and microglia (PMID:23303206)
  • Results suggest that ATP-P2X4 signaling mediates high glucose-induced activation of the NLRP3 inflammasome. (PMID:23434541)
  • P2X4 assembles with P2X7 and pannexin-1 in gingival epithelial cells and modulates ATP-induced reactive oxygen species production and inflammasome activation during P. gingivalis infection. (PMID:23936165)
  • Data indicate that MgATP2- activates P2X1 and P2X3, but not P2X2 and P2X4 receptors. (PMID:23959888)
  • the lysosome-localized P2X4 may play specific roles in membrane trafficking of acidic organelles in mammalian cells. (PMID:24817123)
  • These data suggest that vascular smooth muscle cells from human gastro-omental arteries express P2X1 and P2X4 receptor subunits (PMID:24845338)
  • Using pHluorin, P2X4 was found to be expressed on the plasma membrane and within subcellular compartments in hippocampus. (PMID:24935743)
  • It appears to mediate the cells’ response to extracellular ATP. Although Ca2thorn influx via P2X1 receptor is necessary for alpha-synuclein accumulation. (PMID:25480524)

Cross-species orthologs

3 orthologs

OrganismSymbolGene ID
danio_reriop2rx4aENSDARG00000044752
mus_musculusP2rx4ENSMUSG00000029470
rattus_norvegicusP2rx4ENSRNOG00000001300

Paralogs (6): P2RX5 (ENSG00000083454), P2RX7 (ENSG00000089041), P2RX6 (ENSG00000099957), P2RX1 (ENSG00000108405), P2RX3 (ENSG00000109991), P2RX2 (ENSG00000187848)

Protein

Protein identifiers

P2X purinoceptor 4 — Q99571 (reviewed: Q99571)

Alternative names: ATP receptor, Purinergic receptor

All UniProt accessions (5): F5GZQ9, F5H1M6, F5H2S3, Q99571, H0YF70

UniProt curated annotations — full annotation on UniProt →

Function. ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and calcium. CTP, but not GTP or UTP, functions as a weak affinity agonist for P2RX4. Activated by extracellularly released ATP, it plays multiple role in immunity and central nervous system physiology. Plays a key role in initial steps of T-cell activation and Ca(2+) microdomain formation. Also participates in basal T-cell activity without TCR/CD3 stimulation. Promotes the differentiation and activation of Th17 cells via expression of retinoic acid-related orphan receptor C/RORC. Upon activation, drives microglia motility via the PI3K/Akt pathway. Could also function as an ATP-gated cation channel of lysosomal membranes.

Subunit / interactions. Functional P2RXs are organized as homomeric and heteromeric trimers. Forms heterotrimer with P2RX1. Interacts with P2RX7 (via C-terminus); this interaction is functional only in the presence of ATP. Forms heterotrimer with P2RX4; functional differences between homomeric P2RX4 and P2RX4/6 heterotrimer are minor. Interacts with AP1M2.

Subcellular location. Cell membrane. Lysosome membrane.

Activity regulation. Activated by ATP. pH-dependent and inhibited by acidic pH.

Similarity. Belongs to the P2X receptor family.

Isoforms (3)

UniProt IDNamesCanonical?
Q99571-11yes
Q99571-22
Q99571-33

RefSeq proteins (4): NP_001243725, NP_001248326, NP_001248327, NP_002551* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR001429P2X_purnocptorFamily
IPR003047P2X4_purnocptorFamily
IPR027309P2X_extracellular_dom_sfHomologous_superfamily
IPR053792P2X_RECEPTOR_CSConserved_site
IPR059116P2X_receptorFamily

Pfam: PF00864

Catalyzed reactions (Rhea), 3 shown:

  • K(+)(in) = K(+)(out) (RHEA:29463)
  • Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
  • Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (80 total): strand 21, binding site 13, helix 12, glycosylation site 6, disulfide bond 5, sequence variant 5, turn 5, sequence conflict 4, topological domain 3, transmembrane region 2, splice variant 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDBMethodResolution (Å)
9BQHELECTRON MICROSCOPY2.27
9C48ELECTRON MICROSCOPY2.4
9BQIELECTRON MICROSCOPY2.55
9GP7ELECTRON MICROSCOPY3.35

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q99571-F189.430.66

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 (13): 186; 186; 188; 293; 293; 295; 295; 313; 313; 67; 67; 69 …

Disulfide bonds (5): 116–165, 126–149, 132–159, 217–227, 261–270

Glycosylation sites (6): 75, 110, 153, 184, 199, 208

Mutagenesis-validated functional residues (1):

PositionPhenotype
119does not change atp-induced inward current. does not change affinity for atp.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

IDPathway
R-HSA-139853Elevation of cytosolic Ca2+ levels
R-HSA-418346Platelet homeostasis
R-HSA-9660826Purinergic signaling in leishmaniasis infection

MSigDB gene sets: 458 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MODULE_328, GOBP_REGULATION_OF_ICOSANOID_SECRETION, GOBP_RESPONSE_TO_ZINC_ION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_CHEMOTAXIS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_PROSTAGLANDIN_SECRETION, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT

GO Biological Process (40): tissue homeostasis (GO:0001894), regulation of sodium ion transport (GO:0002028), response to ischemia (GO:0002931), signal transduction (GO:0007165), regulation of blood pressure (GO:0008217), positive regulation of calcium ion transport into cytosol (GO:0010524), negative regulation of cardiac muscle hypertrophy (GO:0010614), sensory perception of pain (GO:0019233), calcium-mediated signaling (GO:0019722), positive regulation of prostaglandin secretion (GO:0032308), response to ATP (GO:0033198), monoatomic ion transmembrane transport (GO:0034220), response to fluid shear stress (GO:0034405), purinergic nucleotide receptor signaling pathway (GO:0035590), endothelial cell activation (GO:0042118), positive regulation of blood vessel endothelial cell migration (GO:0043536), positive regulation of nitric oxide biosynthetic process (GO:0045429), behavioral response to pain (GO:0048266), response to axon injury (GO:0048678), positive regulation of calcium-mediated signaling (GO:0050850), regulation of chemotaxis (GO:0050920), sensory perception of touch (GO:0050975), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), membrane depolarization (GO:0051899), positive regulation of calcium ion transport (GO:0051928), regulation of cardiac muscle contraction (GO:0055117), relaxation of cardiac muscle (GO:0055119), calcium ion transmembrane transport (GO:0070588), cellular response to zinc ion (GO:0071294), cellular response to ATP (GO:0071318), apoptotic signaling pathway (GO:0097190), positive regulation of microglial cell migration (GO:1904141), positive regulation of endothelial cell chemotaxis (GO:2001028), monoatomic ion transport (GO:0006811), response to stress (GO:0006950), regulation of metal ion transport (GO:0010959), positive regulation of cell migration (GO:0030335), excitatory postsynaptic potential (GO:0060079), monoatomic cation transmembrane transport (GO:0098655), positive regulation of intracellular signal transduction (GO:1902533)

GO Molecular Function (13): purinergic nucleotide receptor activity (GO:0001614), extracellularly ATP-gated monoatomic cation channel activity (GO:0004931), signaling receptor binding (GO:0005102), copper ion binding (GO:0005507), ATP binding (GO:0005524), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), cadherin binding (GO:0045296), ligand-gated calcium channel activity (GO:0099604), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), protein binding (GO:0005515), channel activity (GO:0015267)

GO Cellular Component (10): lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), membrane (GO:0016020), cell junction (GO:0030054), cell body (GO:0044297), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), postsynapse (GO:0098794), lysosome (GO:0005764), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-3 pathways:

CategoryPathways
Platelet calcium homeostasis1
Hemostasis1
Cell recruitment (pro-inflammatory response)1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure6
response to stress2
calcium-mediated signaling2
ligand-gated monoatomic cation channel activity2
protein binding2
transition metal ion binding2
multicellular organismal-level homeostasis1
anatomical structure homeostasis1
sodium ion transport1
regulation of metal ion transport1
cell communication1
cellular process1
signaling1
regulation of cellular process1
cellular response to stimulus1
blood circulation1
regulation of biological quality1
positive regulation of cytosolic calcium ion concentration1
regulation of calcium ion transport into cytosol1
calcium ion transport into cytosol1
positive regulation of calcium ion transmembrane transport1
cardiac muscle hypertrophy1
regulation of cardiac muscle hypertrophy1
negative regulation of muscle hypertrophy1
sensory perception1
intracellular signaling cassette1
positive regulation of icosanoid secretion1
regulation of prostaglandin secretion1
prostaglandin secretion1
positive regulation of secretion by cell1
response to purine-containing compound1
response to organophosphorus1
response to oxygen-containing compound1
monoatomic ion transport1
transmembrane transport1
cell surface receptor signaling pathway1
cell activation1
positive regulation of endothelial cell migration1
blood vessel endothelial cell migration1
regulation of blood vessel endothelial cell migration1

Protein interactions and networks

STRING

1034 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
P2RX4P2RX7Q99572946
P2RX4P2RX6O15547931
P2RX4P2RX3P56373917
P2RX4P2RX2Q9UBL9885
P2RX4PANX1Q96RD7855
P2RX4P2RY2P41231849
P2RX4P2RY12Q9H244792
P2RX4PLA2G1BP04054782
P2RX4P2RX5Q93086775
P2RX4P2RY6Q15077763
P2RX4P2RX1P51575762
P2RX4P2RY4P51582756
P2RX4ASIC1P78348753
P2RX4P2RY11Q96G91742
P2RX4A0A0B4J1V8A0A0B4J1V8740

IntAct

50 interactions, top by confidence:

ABTypeScore
P2RX4FAM20Bpsi-mi:“MI:0914”(association)0.640
SLC16A3CASKpsi-mi:“MI:0914”(association)0.590
KRTAP5-9P2RX4psi-mi:“MI:0915”(physical association)0.560
P2RX4NOTCH2NLApsi-mi:“MI:0915”(physical association)0.560
DNAAF6P2RX4psi-mi:“MI:0915”(physical association)0.560
NOTCH2NLAP2RX4psi-mi:“MI:0915”(physical association)0.560
NOTCH2NLCP2RX4psi-mi:“MI:0915”(physical association)0.560
KRTAP1-1P2RX4psi-mi:“MI:0915”(physical association)0.560
KRTAP12-3P2RX4psi-mi:“MI:0915”(physical association)0.560
SPPL2BUQCRQpsi-mi:“MI:0914”(association)0.530
CSGALNACT2GOLIM4psi-mi:“MI:0914”(association)0.530
CCR6PODXLpsi-mi:“MI:0914”(association)0.530
CSGALNACT2TPST1psi-mi:“MI:0914”(association)0.530
P2RX4MCM2psi-mi:“MI:0915”(physical association)0.370
P2RX4WNT4psi-mi:“MI:0915”(physical association)0.370
CSGALNACT2CLASP2psi-mi:“MI:0914”(association)0.350
P2RX4ORC4psi-mi:“MI:0914”(association)0.350
TTMPTMEM223psi-mi:“MI:0914”(association)0.350
OPRL1METTL15psi-mi:“MI:0914”(association)0.350
SPPL2BGPR89Apsi-mi:“MI:0914”(association)0.350
B3GALT5TTI1psi-mi:“MI:0914”(association)0.350
SPPL2BHAS3psi-mi:“MI:0914”(association)0.350
CYBC1NDUFV3psi-mi:“MI:0914”(association)0.350

BioGRID (88): P2RX4 (Two-hybrid), PIH1D3 (Two-hybrid), NOTCH2NL (Two-hybrid), C17orf62 (Affinity Capture-MS), EIF2B5 (Affinity Capture-MS), EMC1 (Affinity Capture-MS), FDFT1 (Affinity Capture-MS), ARMCX3 (Affinity Capture-MS), FAM20B (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS), GALNT1 (Affinity Capture-MS), SPTLC2 (Affinity Capture-MS), TMEM246 (Affinity Capture-MS), HS2ST1 (Affinity Capture-MS), PIGH (Affinity Capture-MS)

ESM2 similar proteins: A2X2H7, A2XHZ9, A9SV59, F4HXW9, F4IAX0, F4IAX1, O04500, O23349, O80844, P0DO00, P41439, P45582, P50699, P51577, Q0DZ85, Q10JL1, Q10NX8, Q53MB8, Q5DWG1, Q5E9U1, Q5N8X6, Q60E70, Q6Z4G7, Q6Z4G8, Q6Z6K4, Q75IW1, Q7XR91, Q84TW8, Q8GZ17, Q8H1E6, Q8H1H9, Q8L8Q7, Q8W3E8, Q93Z08, Q94KT8, Q94LR4, Q99571, Q9C6E4, Q9FE06, Q9FHM9

Diamond homologs: F8W463, O15547, O54803, O70397, P47824, P49653, P49654, P51575, P51576, P51577, P51578, P51579, P56373, Q3UR32, Q5E9U1, Q64663, Q8K3P1, Q91VE2, Q93086, Q99571, Q99572, Q9JJX6, Q9UBL9, Q9Z1M0, Q86JM7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance49
Likely benign4
Benign4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1989 predictions. Top by Δscore:

VariantEffectΔscore
12:121210295:TCGGG:Tdonor_loss1.0000
12:121210297:GG:Gdonor_gain1.0000
12:121210297:GGGTG:Gdonor_loss1.0000
12:121210298:GG:Gdonor_gain1.0000
12:121210298:GGTGA:Gdonor_loss1.0000
12:121210299:G:GGdonor_gain1.0000
12:121210299:GT:Gdonor_loss1.0000
12:121210300:T:Adonor_loss1.0000
12:121232409:CTCAG:Cacceptor_loss1.0000
12:121232410:TCAG:Tacceptor_loss1.0000
12:121232411:CAG:Cacceptor_loss1.0000
12:121232412:A:ACacceptor_loss1.0000
12:121232412:A:AGacceptor_gain1.0000
12:121232413:G:Aacceptor_loss1.0000
12:121232413:G:GGacceptor_gain1.0000
12:121232469:GCC:Gdonor_gain1.0000
12:121232504:G:GTdonor_gain1.0000
12:121232504:GAAGG:Gdonor_loss1.0000
12:121232505:A:Tdonor_gain1.0000
12:121232505:AAG:Adonor_loss1.0000
12:121232506:AG:Adonor_loss1.0000
12:121232507:GGTAG:Gdonor_loss1.0000
12:121232508:G:Adonor_loss1.0000
12:121232509:T:Adonor_loss1.0000
12:121232597:C:CAacceptor_gain1.0000
12:121232994:CAG:Cacceptor_loss1.0000
12:121232995:A:AGacceptor_gain1.0000
12:121232996:G:GCacceptor_loss1.0000
12:121232996:G:GTacceptor_gain1.0000
12:121232996:GGC:Gacceptor_gain1.0000

AlphaMissense

2564 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
12:121223011:G:CW164C0.998
12:121223011:G:TW164C0.998
12:121228990:T:AW259R0.998
12:121228990:T:CW259R0.998
12:121228992:G:CW259C0.998
12:121228992:G:TW259C0.998
12:121233013:A:CD354A0.998
12:121233013:A:TD354V0.998
12:121210207:T:CY15H0.997
12:121223009:T:AW164R0.997
12:121223009:T:CW164R0.997
12:121228996:T:AC261S0.997
12:121228997:G:CC261S0.997
12:121232651:G:AG340D0.997
12:121232663:C:AA344E0.997
12:121210262:G:CR33P0.996
12:121228731:T:AN204K0.996
12:121228731:T:GN204K0.996
12:121228798:T:AC227S0.996
12:121228798:T:CC227R0.996
12:121228799:G:AC227Y0.996
12:121228799:G:CC227S0.996
12:121228800:C:GC227W0.996
12:121228997:G:AC261Y0.996
12:121228998:C:GC261W0.996
12:121229023:T:AC270S0.996
12:121229024:G:CC270S0.996
12:121229099:G:TR295M0.996
12:121232454:C:AR309S0.996
12:121232482:G:CR318P0.996

dbSNP variants (sampled 300 via entrez): RS1000013156 (12:121228455 G>A), RS1000170918 (12:121232223 G>A,C), RS1000218023 (12:121226528 A>G), RS1000280493 (12:121226971 C>G,T), RS1000353493 (12:121226775 C>A,T), RS1000481283 (12:121209817 C>G,T), RS1000605031 (12:121231860 C>T), RS1001141414 (12:121228632 T>C), RS1001388851 (12:121234458 C>A), RS1001536613 (12:121210708 G>A), RS1001572467 (12:121213306 T>C), RS1001635501 (12:121214502 C>A), RS1001881083 (12:121230876 G>A,C), RS1001914840 (12:121219463 G>T), RS1002027202 (12:121225688 C>A,G,T)

Disease associations

OMIM: gene MIM:600846 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

StudyTraitp-value
GCST004719_15Left ventricular obstructive tract defect (inherited effect)4.000000e-06
GCST010396_175Gut microbiota (bacterial taxa, hurdle binary method)3.000000e-06

EFO canonical traits (1, from GWAS)

EFO IDTrait name
EFO:0007874gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2104 (SINGLE PROTEIN), CHEMBL4524012 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 399,607 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

MoleculeNamePhasePatents
CHEMBL1175DULOXETINE428,527
CHEMBL490PAROXETINE446,410
CHEMBL265502SURAMIN336,848
CHEMBL14249ADENOSINE TRIPHOSPHATE2287,353
CHEMBL536151IMD-03541469

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — P2X receptors

Most potent curated ligand interactions (10 total), top 10:

LigandActionAffinityParameter
BAY-1797Antagonist7.0pIC50
PSB-12054Antagonist6.7pIC50
NP-1815-PXAntagonist6.6pIC50
ivermectinPositive6.6pEC50
paroxetineAntagonist6.0pIC50
5-BDBDAntagonist6.0pIC50
PSB-12062Antagonist6.0pIC50
BX-430Antagonist6.0pIC50
ATPAgonist5.9pEC50
PPADSAntagonist5.0pIC50

Binding affinities (BindingDB)

53 measured of 54 human assays (57 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

LigandMeasureValuePatent
5-[4-[5-(2-Methoxybenzyl)-1H-tetrazol-1-yl]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneIC5025 nMUS-9873683: P2X4 receptor antagonist
5-[4-[5-(2-Hydroxybenzyl)-1H-tetrazol-1-yl]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneIC5037 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-[2-(3-fluorophenyl)ethyl]imidazol-1-yl]phenyl]-1,8,9,10-tetrahydrocyclopenta[i][1,5]benzodiazepine-2,4-dioneIC5039 nMUS-9873683: P2X4 receptor antagonist
5-[4-(5-Phenethyl-1H-tetrazol-1-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneIC5044 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-[2-(3-fluorophenyl)ethyl]imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC5051 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-[2-(3-hydroxyphenyl)ethyl]imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC5053 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-[2-(2-fluorophenyl)ethyl]imidazol-1-yl]phenyl]-1,8,9,10-tetrahydrocyclopenta[i][1,5]benzodiazepine-2,4-dioneIC5053 nMUS-9873683: P2X4 receptor antagonist
1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1H-benzo[g][1,5]benzodiazepin-5-yl)phenyl]methanesulfonamideIC5064 nMUS-9969700: P2X4 receptor antagonist
5-[4-[2-[2-(3-methoxyphenyl)ethyl]imidazol-1-yl]phenyl]-1,8,9,10-tetrahydrocyclopenta[i][1,5]benzodiazepine-2,4-dioneIC5074 nMUS-9873683: P2X4 receptor antagonist
5-[6-[5-(2-Hydroxybenzyl)-1H-tetrazol-1-yl]pyridin-3-yl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneIC5077 nMUS-9873683: P2X4 receptor antagonist
5-[4-[1-[2-(3-hydroxyphenyl)ethyl]imidazol-2-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC5078 nMUS-9873683: P2X4 receptor antagonist
5-[4-(2-Phenethyl-1H-imidazol-1-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneIC5078 nMUS-9873683: P2X4 receptor antagonist
NSC_8272KI78.3 nM
5-[4-[2-[2-(2,6-dimethylphenyl)ethyl]imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC5079 nMUS-9873683: P2X4 receptor antagonist
5-[4-[1-[2-(3-methoxyphenyl)ethyl]imidazol-2-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC5082 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-[2-(3-fluoro-2-methoxyphenyl)ethyl]imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC5087 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-(2-thiophen-3-ylethyl)imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC5088 nMUS-9873683: P2X4 receptor antagonist
5-[4-[1-(2-phenylethyl)imidazol-2-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC5091 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-[2-(3-methoxyphenyl)ethyl]imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC5092 nMUS-9873683: P2X4 receptor antagonist
5-[4-[5-[[2-(dimethylamino)phenyl]methyl]tetrazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC5094 nMUS-9873683: P2X4 receptor antagonist
3-[2-[1-[4-(2,4-dioxo-1H-benzo[g][1,5]benzodiazepin-5-yl)phenyl]imidazol-2-yl]ethyl]benzamideIC50130 nMUS-9873683: P2X4 receptor antagonist
5-[3-hydroxy-4-[1-(2-phenylethyl)imidazol-2-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50130 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-[2-(2-methoxyphenyl)ethyl]imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50180 nMUS-9873683: P2X4 receptor antagonist
2-[2-[1-[4-(2,4-dioxo-1H-benzo[g][1,5]benzodiazepin-5-yl)phenyl]imidazol-2-yl]ethyl]benzonitrileIC50190 nMUS-9873683: P2X4 receptor antagonist
5-[4-[5-[2-(6-methyl-2-pyridinyl)ethyl]tetrazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50270 nMUS-9873683: P2X4 receptor antagonist
5-[4-[1-[(4-chlorophenyl)methyl]imidazol-2-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50300 nMUS-9873683: P2X4 receptor antagonist
5-[4-[1-(2-phenylethyl)imidazol-4-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50320 nMUS-9873683: P2X4 receptor antagonist
5-[4-[5-(2-Methoxybenzyl)-1H-tetrazol-1-yl]phenyl]-1H-naphtho[1,2-e][1,4]diazepin-2(3H)-oneIC50320 nMUS-9873683: P2X4 receptor antagonist
2-[2-[1-[4-(2,4-dioxo-1H-benzo[g][1,5]benzodiazepin-5-yl)phenyl]imidazol-2-yl]ethyl]benzamideIC50340 nMUS-9873683: P2X4 receptor antagonist
5-[4-[5-[2-(Pyridin-3-yl)ethyl]-1H-tetrazol-1-yl]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneIC50380 nMUS-9873683: P2X4 receptor antagonist
5-[4-[(2-iodophenyl)methylamino]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50430 nMUS-9969700: P2X4 receptor antagonist
1-(2-chlorophenyl)-N-[4-(2-oxo-1,3-dihydrobenzo[i][1,4]benzodiazepin-5-yl)phenyl]methanesulfonamideIC50440 nMUS-9969700: P2X4 receptor antagonist
5-[3-methoxy-4-[1-(2-phenylethyl)imidazol-2-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50520 nMUS-9873683: P2X4 receptor antagonist
2-(2-chlorophenyl)-N-[4-(2,4-dioxo-1H-benzo[g][1,5]benzodiazepin-5-yl)phenyl]acetamideIC50540 nMUS-9969700: P2X4 receptor antagonist
5-[4-[2-[2-[3-(trifluoromethyl)phenyl]ethyl]imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50550 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-[2-(furan-2-yl)ethyl]imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50550 nMUS-9873683: P2X4 receptor antagonist
2-[[2-[4-(2,4-dioxo-1H-benzo[g][1,5]benzodiazepin-5-yl)phenyl]imidazol-1-yl]methyl]benzamideIC50590 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-(2-pyridin-2-ylethyl)imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50590 nMUS-9873683: P2X4 receptor antagonist
5-[4-[5-(2-phenylethyl)tetrazol-1-yl]phenyl]-1,3-dihydrobenzo[i][1,4]benzodiazepin-2-oneIC50630 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-(2-phenylethyl)imidazol-1-yl]phenyl]-1,3-dihydrobenzo[i][1,4]benzodiazepin-2-oneIC50650 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-(phenoxymethyl)imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC50790 nMUS-9873683: P2X4 receptor antagonist
Cibacron Blue 3GaKI800 nM
1-(2-chlorophenyl)-N-[4-(2,4-dioxo-8,9,10,11-tetrahydro-1H-benzo[i][1,5]benzodiazepin-5-yl)phenyl]-N-methylmethanesulfonamideIC50970 nMUS-9969700: P2X4 receptor antagonist
1-[4-(2,4-dioxo-1H-benzo[g][1,5]benzodiazepin-5-yl)phenyl]-3-phenylureaIC501200 nMUS-9969700: P2X4 receptor antagonist
5-[4-[2-(anilinomethyl)imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC501300 nMUS-9873683: P2X4 receptor antagonist
5-[4-[2-(2-methoxyphenyl)imidazol-1-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC501700 nMUS-9873683: P2X4 receptor antagonist
N-[4-(2,4-dioxo-5a,6,7,7a,8,9,10,11,11a,11b-decahydro-1H-naphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-(2-iodophenyl)acetamideIC501800 nMUS-9969700: P2X4 receptor antagonist
5-[4-[5,5-dimethyl-2-(2-phenylethyl)-4H-imidazol-3-yl]phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC502500 nMUS-9873683: P2X4 receptor antagonist
5-[4-(4-phenyl-1H-imidazol-5-yl)phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC503400 nMUS-9873683: P2X4 receptor antagonist
5-[4-(2-phenylimidazol-1-yl)phenyl]-1H-benzo[g][1,5]benzodiazepine-2,4-dioneIC503700 nMUS-9873683: P2X4 receptor antagonist

ChEMBL bioactivities

372 potent at pChembl≥5 of 433 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
8.70IC502nMCHEMBL4471140
8.70IC502nMCHEMBL4452312
8.30IC505nMCHEMBL4589444
8.12IC507.586nMCHEMBL6133296
8.10IC508nMCHEMBL4579583
8.10IC508nMCHEMBL6133296
8.05IC509nMCHEMBL4447043
8.00IC5010nMCHEMBL4556573
8.00IC5010nMCHEMBL4522504
7.89IC5013nMCHEMBL4555657
7.89IC5013nMCHEMBL4516176
7.86IC5013.8nMCHEMBL6167329
7.85IC5014nMCHEMBL6167329
7.82IC5015nMCHEMBL4521017
7.82IC5015.14nMCHEMBL6143541
7.82IC5015nMCHEMBL6143541
7.77IC5017nMCHEMBL6148511
7.76IC5017.38nMCHEMBL6148511
7.72IC5019nMCHEMBL4563994
7.64IC5023nMCHEMBL6171122
7.63IC5023.44nMCHEMBL6171122
7.62IC5024nMCHEMBL4438327
7.60IC5025nMCHEMBL5778042
7.60IC5025.12nMCHEMBL6161496
7.60IC5025nMCHEMBL6161496
7.58IC5026nMCHEMBL4439570
7.57IC5027nMCHEMBL4535761
7.52IC5030nMCHEMBL4463320
7.43IC5037nMCHEMBL4517831
7.43IC5037nMCHEMBL6044943
7.41IC5039nMCHEMBL4539658
7.41IC5039nMCHEMBL5206892
7.41IC5039nMCHEMBL5962303
7.40IC5040nMCHEMBL5204261
7.37IC5042.6nMCHEMBL4640175
7.36IC5044nMCHEMBL5941457
7.35IC5045nMCHEMBL4474747
7.32IC5047.86nMCHEMBL6170380
7.32IC5048nMCHEMBL6170380
7.31Ki48.9nMTNP-ATP
7.31IC5048.8nMCHEMBL2338695
7.29IC5051nMCHEMBL6043992
7.28IC5052nMCHEMBL4443234
7.28IC5053nMCHEMBL6033809
7.28IC5053nMCHEMBL6026605
7.27IC5054nMCHEMBL4557633
7.26IC5055nMCHEMBL5200114
7.26IC5054.95nMCHEMBL4557633
7.26IC5055nMCHEMBL4557633
7.23IC5058.88nMCHEMBL6146423

PubChem BioAssay actives

168 with measured affinity, of 510 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.

CompoundAssayTypeValueUnit
2-(2-chlorophenyl)-N-(4-phenylmethoxy-3-sulfamoylphenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0020uM
N-[4-(3-chlorophenoxy)-3-sulfamoylphenyl]-2-(2-methoxyphenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0020uM
2-(2-chlorophenyl)-N-[4-(cyclobutylmethoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0050uM
2-(2-chlorophenyl)-N-[4-(3-methoxyphenoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0080uM
2-(2-chloro-6-fluorophenyl)-N-[4-(3-chlorophenoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0090uM
2-(2-chlorophenyl)-N-(4-phenoxy-3-sulfamoylphenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0100uM
N-[4-(3-chlorophenoxy)-3-sulfamoylphenyl]-2-(2-methylphenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0100uM
2-(2-chloro-6-fluorophenyl)-N-[4-(oxan-4-ylmethoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0130uM
N-[4-(2-chlorophenoxy)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0130uM
N-[4-(3-chlorophenoxy)-3-sulfamoylphenyl]-2-(2,6-dichlorophenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0150uM
2-(2-chlorophenyl)-N-[4-(2-phenylethoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0190uM
N-[4-(3-chlorophenoxy)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0240uM
2-(2-chlorophenyl)-N-[4-(pyridin-2-ylmethoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0260uM
2-(2-chlorophenyl)-N-[4-[(5-chloro-3-pyridinyl)oxy]-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0270uM
2-(2-chlorophenyl)-N-[3-sulfamoyl-4-[4-(1,3-thiazol-2-yl)phenoxy]phenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0300uM
2-(2-chloro-3-fluorophenyl)-N-[4-(oxan-4-ylmethoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0370uM
2-(2-chlorophenyl)-N-(4-cyclohexyloxy-3-sulfamoylphenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0390uM
N-[(2-bromo-4-propan-2-ylphenyl)carbamothioyl]-1,3-benzodioxole-5-carboxamide1884357: Antagonist activity against human P2X4R stably transfected in human 1321N1 cells incubated for 30 mins by Fura-2 AM staining based calcium influx assayic500.0390uM
N-[(2-bromo-4-propan-2-ylphenyl)carbamothioyl]adamantane-1-carboxamide1879257: Negative allosteric modulation activity at human P2X4 receptor expressed in human 1321N1 cells assessed as reduction in intracellular Ca2+ influx incubated for 30 mins by Fura-2 AM based fluorescence assayic500.0400uM
5-chloro-2-hydroxy-N-[3-nitro-5-(trifluoromethyl)phenyl]benzamide1654788: Antagonist activity at human P2X4 receptor expressed in human 1321N1 cells assessed as inhibition of ATP-induced cytosolic calcium influx preincubated for 30 mins followed by ATP addition by Fluo-4 AM dye-based fluorescence assayic500.0426uM
2-(2-chlorophenyl)-N-[4-[3-(morpholine-4-carbonyl)phenoxy]-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0450uM
N-[3,5-bis(trifluoromethyl)phenyl]-3-chloro-2-hydroxybenzamide1654788: Antagonist activity at human P2X4 receptor expressed in human 1321N1 cells assessed as inhibition of ATP-induced cytosolic calcium influx preincubated for 30 mins followed by ATP addition by Fluo-4 AM dye-based fluorescence assayic500.0488uM
[[(3aR,4R,6R,6aR)-4-(6-aminopurin-9-yl)-1’,3’,5’-trinitrospiro[3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole-2,6’-cyclohexa-1,3-diene]-6-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate709138: Competitive antagonist activity at human P2X4 receptor expressed in 1321N1 cell membrane assessed as inhibition of [35S]ATPgammaS binding by scintillation countingki0.0489uM
N-[4-(3-chlorophenoxy)-3-sulfamoylphenyl]-2-(3-methylphenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0520uM
1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1H-benzo[g][1,5]benzodiazepin-5-yl)phenyl]methanesulfonamide1528202: Antagonist activity at human P2X4 receptor expressed in HEK cells assessed as reduction in ATP induced calcium influxic500.0540uM
N-[[2,6-dibromo-3-(trifluoromethyl)phenyl]carbamothioyl]-1,3-benzodioxole-5-carboxamide1884357: Antagonist activity against human P2X4R stably transfected in human 1321N1 cells incubated for 30 mins by Fura-2 AM staining based calcium influx assayic500.0550uM
2-(2-chlorophenyl)-N-[3-sulfamoyl-4-[3-(1,2,4-triazol-4-yl)phenoxy]phenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0670uM
2-(2-chlorophenyl)-N-[4-[4-(oxolan-3-yl)phenoxy]-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0750uM
N-[4-(3-chlorophenoxy)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0760uM
2-(2-chloro-5-fluorophenyl)-N-[4-(oxan-4-ylmethoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0840uM
N-[4-(oxan-4-ylmethoxy)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0880uM
N-[4-(3-chlorophenoxy)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0920uM
N-[4-(3-acetamidophenoxy)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.0930uM
3-methyl-4-[3-(2H-tetrazol-5-yl)phenyl]-1,5-dihydropyrido[3,2-b]indol-2-one1528202: Antagonist activity at human P2X4 receptor expressed in HEK cells assessed as reduction in ATP induced calcium influxic500.1000uM
N-[4-(3-chlorophenoxy)-3-sulfamoylphenyl]-2-phenylacetamide1528176: Antagonist activity at human P2X4 receptor tranfected in human 1321N1 cells assessed as inhibition of Mg-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.1080uM
2-[2-(difluoromethyl)phenyl]-N-[4-(oxan-4-ylmethoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.1110uM
N-[4-(3-chlorophenoxy)-3-sulfamoylphenyl]-2-(2-chlorophenyl)propanamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.1340uM
5-chloro-N-(3-chlorophenyl)-2-hydroxybenzamide1654788: Antagonist activity at human P2X4 receptor expressed in human 1321N1 cells assessed as inhibition of ATP-induced cytosolic calcium influx preincubated for 30 mins followed by ATP addition by Fluo-4 AM dye-based fluorescence assayic500.1350uM
2-(2-chlorophenyl)-N-[4-(oxan-4-ylmethoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.1390uM
N-[2-[acetyl(1,3-benzoxazol-6-yl)amino]-4-pyridinyl]-2-(2,6-dichlorophenyl)acetamide1880264: Inhibition of human P2X4 stably expressed in human HEK293 cells assessed as intracellular calcium flux incubated for 30 mins in presence of agonist Benzoylbenzoyl-ATP by Fluo8-AM dye based FLIPR assayic500.1410uM
N-[2-[acetyl(1,3-benzothiazol-6-yl)amino]-4-pyridinyl]-2-(2-chlorophenyl)acetamide1880264: Inhibition of human P2X4 stably expressed in human HEK293 cells assessed as intracellular calcium flux incubated for 30 mins in presence of agonist Benzoylbenzoyl-ATP by Fluo8-AM dye based FLIPR assayic500.1420uM
N-[2-[acetyl(1,3-benzoxazol-6-yl)amino]-4-pyridinyl]-2-(2-chloro-3-fluorophenyl)acetamide1880264: Inhibition of human P2X4 stably expressed in human HEK293 cells assessed as intracellular calcium flux incubated for 30 mins in presence of agonist Benzoylbenzoyl-ATP by Fluo8-AM dye based FLIPR assayic500.1430uM
5-chloro-N-(3,5-difluorophenyl)-2-hydroxybenzamide1654788: Antagonist activity at human P2X4 receptor expressed in human 1321N1 cells assessed as inhibition of ATP-induced cytosolic calcium influx preincubated for 30 mins followed by ATP addition by Fluo-4 AM dye-based fluorescence assayic500.1550uM
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide1654788: Antagonist activity at human P2X4 receptor expressed in human 1321N1 cells assessed as inhibition of ATP-induced cytosolic calcium influx preincubated for 30 mins followed by ATP addition by Fluo-4 AM dye-based fluorescence assayic500.1550uM
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide1654788: Antagonist activity at human P2X4 receptor expressed in human 1321N1 cells assessed as inhibition of ATP-induced cytosolic calcium influx preincubated for 30 mins followed by ATP addition by Fluo-4 AM dye-based fluorescence assayic500.1560uM
N-[2-[acetyl(pyrazolo[1,5-a]pyridin-5-yl)amino]-4-pyridinyl]-2-(2,6-dichlorophenyl)acetamide1880264: Inhibition of human P2X4 stably expressed in human HEK293 cells assessed as intracellular calcium flux incubated for 30 mins in presence of agonist Benzoylbenzoyl-ATP by Fluo8-AM dye based FLIPR assayic500.1570uM
2-(2-chlorophenyl)-N-[4-[3-(3-oxomorpholin-4-yl)phenoxy]-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.1630uM
N-[2-[acetyl(1,3-benzoxazol-6-yl)amino]-4-pyridinyl]-2-(2-chlorophenyl)acetamide1880264: Inhibition of human P2X4 stably expressed in human HEK293 cells assessed as intracellular calcium flux incubated for 30 mins in presence of agonist Benzoylbenzoyl-ATP by Fluo8-AM dye based FLIPR assayic500.1680uM
N-[2-[acetyl-(3-fluoro-4-pyridinyl)amino]-4-pyridinyl]-2-(2,6-dichlorophenyl)acetamide1880264: Inhibition of human P2X4 stably expressed in human HEK293 cells assessed as intracellular calcium flux incubated for 30 mins in presence of agonist Benzoylbenzoyl-ATP by Fluo8-AM dye based FLIPR assayic500.1710uM
2-(2-chloro-4-fluorophenyl)-N-[4-(oxan-4-ylmethoxy)-3-sulfamoylphenyl]acetamide1528149: Antagonist activity at human P2X4 receptor tranfected in HEK293 cells assessed as inhibition of Bz-ATP-induced calcium influx incubated for 30 mins and measured every 2 secs for 120 secs by Fluo8-AM staining based FLIPR assayic500.1730uM

CTD chemical–gene interactions

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

ChemicalActions (top 5)PubMed papers
Valproic Acidaffects cotreatment, decreases expression, affects expression6
Adenosine Triphosphatedecreases reaction, increases activity, affects cotreatment, increases reaction, increases expression4
Air Pollutantsincreases abundance, affects expression, increases expression, decreases expression, affects methylation4
sodium arseniteaffects splicing, decreases expression, affects cotreatment, increases abundance3
Resveratrolaffects cotreatment, increases expression2
Arsenicincreases abundance, affects methylation, affects cotreatment, decreases expression2
Benzo(a)pyreneaffects methylation, increases expression2
Estradiolaffects binding, increases reaction, decreases expression2
FR900359increases phosphorylation1
coomassie Brilliant Bluedecreases reaction, increases activity, decreases activity1
bisphenol Adecreases expression1
trichostatin Adecreases expression1
manganese chlorideaffects cotreatment, decreases expression, increases abundance1
hydroquinoneincreases expression1
ginsenoside Rdincreases activity, increases reaction1
perfluorooctane sulfonic acidincreases expression1
ginsenoside compound Kincreases activity, increases reaction, affects cotreatment1
K 7174increases expression1
ginsenoside Rb1increases activity, increases reaction1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, decreases expression1
ICG 001increases expression1
dorsomorphinaffects cotreatment, decreases expression1
jinfukangincreases expression1
5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro(3,2-e)-1,4-diazepin-2-onedecreases reaction, increases activity, decreases activity1
Temozolomideincreases expression1
Zoledronic Acidincreases expression1
Acetaminophenincreases expression1
Benzeneincreases expression1
Benzoatesincreases expression1
Cadmiumincreases expression1

ChEMBL screening assays

106 unique, capped per target: 94 binding, 12 functional

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL1017979FunctionalAntagonist activity at P2X4 receptor up to 10 uMIdentification and SAR of novel diaminopyrimidines. Part 2: The discovery of RO-51, a potent and selective, dual P2X(3)/P2X(2/3) antagonist for the treatment of pain. — Bioorg Med Chem Lett
CHEMBL1925629BindingInhibition of P2X4 receptor at 10 uMSynthesis and SAR development of novel P2X7 receptor antagonists for the treatment of pain: part 2. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 transformed cell line

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

CellosaurusNameCategorySex
CVCL_C0YLB’SYS HEK 293 P2X4Transformed cell lineFemale
CVCL_D7WDUbigene A-549 P2RX4 KOCancer cell lineMale
CVCL_D8RWUbigene HCT 116 P2RX4 KOCancer cell lineMale
CVCL_D9M1Ubigene HEK293 P2RX4 KOTransformed cell lineFemale
CVCL_E0JMUbigene HeLa P2RX4 KOCancer cell lineFemale

Clinical trials (associated diseases)

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

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
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v2.0.2

Sources 81

This page pulls from 81 datasets indexed by BioBTree:

alphafoldalphamissenseantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticsccdscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetciviccivic_evidenceclingen_dosageclingen_gene_validityclinical_trialsclinvarcollectrictd_gene_interactiondbsnpdepmapdiamond_similarityefoensemblentrezesm2_similarityexonfantom5_genefantom5_promotergenccgenerifgogoparentgtopdbgtopdb_interactiongwasgwas_studyhgnchpointactinterprointogenjasparmeshmimmirdbmondomsigdborphanetorthologparalogpatentpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assaypubmedreactomereactomeparentrefseqrhearnacentralscxa_expressionscxa_gene_experimentsignorspliceaistring_interactiontranscriptufeatureuniprot