GPR4
gene geneOn this page
Summary
GPR4 (G protein-coupled receptor 4, HGNC:4497) is a protein-coding gene on chromosome 19q13.32, encoding G-protein coupled receptor 4 (P46093). Proton-sensing G-protein coupled receptor activated by extracellular pH, which is required to monitor pH changes and generate adaptive reactions.
Enables G protein-coupled receptor activity. Involved in several processes, including G protein-coupled receptor signaling pathway; positive regulation of Rho protein signal transduction; and response to acidic pH. Located in plasma membrane.
Source: NCBI Gene 2828 — RefSeq curated summary.
At a glance
- Clinical variants (ClinVar): 44 total
- Druggable target: yes
- MANE Select transcript:
NM_005282
Identifiers
Gene identifiers
| Field | Value |
|---|---|
| HGNC ID | HGNC:4497 |
| Approved symbol | GPR4 |
| Name | G protein-coupled receptor 4 |
| Location | 19q13.32 |
| Locus type | gene with protein product |
| Status | Approved |
| Ensembl gene | ENSG00000177464 |
| Ensembl biotype | protein_coding |
| OMIM | 600551 |
| Entrez | 2828 |
Gene structure
Transcript identifiers
Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined
ENST00000323040, ENST00000591614, ENST00000877384, ENST00000877385, ENST00000877386, ENST00000877387, ENST00000877388, ENST00000877389
RefSeq mRNA: 1 — MANE Select: NM_005282
NM_005282
CCDS: CCDS12669
Canonical transcript exons
ENST00000323040 — 2 exons
| Exon | Start | End |
|---|---|---|
| ENSE00001402778 | 45602095 | 45602212 |
| ENSE00001414097 | 45589764 | 45592697 |
Expression profiles
Bgee: expression breadth ubiquitous, 207 present calls, max score 90.41.
FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2796 / max 108.5483, expressed in 134 samples.
FANTOM5 promoters (3 alternative TSS)
| Promoter ID | TPM avg | Samples expressed |
|---|---|---|
| 181537 | 3.7852 | 506 |
| 181535 | 0.2400 | 109 |
| 181536 | 0.0396 | 21 |
Top tissues by expression
277 total, by Bgee expression score (0-100, higher = more expressed):
| Tissue | Anatomy ID | Expression score | Quality |
|---|---|---|---|
| omental fat pad | UBERON:0010414 | 90.41 | gold quality |
| peritoneum | UBERON:0002358 | 90.36 | gold quality |
| adipose tissue of abdominal region | UBERON:0007808 | 89.23 | gold quality |
| upper lobe of left lung | UBERON:0008952 | 86.58 | gold quality |
| right lung | UBERON:0002167 | 86.24 | gold quality |
| upper lobe of lung | UBERON:0008948 | 86.01 | gold quality |
| apex of heart | UBERON:0002098 | 85.21 | gold quality |
| left lobe of thyroid gland | UBERON:0001120 | 84.20 | gold quality |
| right lobe of thyroid gland | UBERON:0001119 | 84.02 | gold quality |
| thyroid gland | UBERON:0002046 | 82.70 | gold quality |
| heart left ventricle | UBERON:0002084 | 82.64 | gold quality |
| cardiac ventricle | UBERON:0002082 | 82.37 | gold quality |
| metanephros cortex | UBERON:0010533 | 82.20 | gold quality |
| pericardium | UBERON:0002407 | 81.81 | gold quality |
| subcutaneous adipose tissue | UBERON:0002190 | 81.65 | gold quality |
| adipose tissue | UBERON:0001013 | 81.53 | gold quality |
| colonic epithelium | UBERON:0000397 | 80.76 | gold quality |
| connective tissue | UBERON:0002384 | 80.53 | gold quality |
| tibial nerve | UBERON:0001323 | 80.34 | gold quality |
| right atrium auricular region | UBERON:0006631 | 80.10 | gold quality |
| hindlimb stylopod muscle | UBERON:0004252 | 79.06 | gold quality |
| heart | UBERON:0000948 | 78.92 | gold quality |
| medial globus pallidus | UBERON:0002477 | 78.88 | gold quality |
| epithelial cell of pancreas | CL:0000083 | 78.86 | gold quality |
| primordial germ cell in gonad | CL:0000670 ∩ UBERON:0000991 | 78.76 | gold quality |
| cardiac atrium | UBERON:0002081 | 78.23 | gold quality |
| left uterine tube | UBERON:0001303 | 78.15 | gold quality |
| lower lobe of lung | UBERON:0008949 | 77.54 | gold quality |
| buccal mucosa cell | CL:0002336 | 77.53 | gold quality |
| globus pallidus | UBERON:0001875 | 77.31 | gold quality |
Single-cell (SCXA)
Detected in 2 experiment(s), a significant marker in 2.
| Experiment | Marker? | Max mean expression |
|---|---|---|
| E-ANND-3 | yes | 11.03 |
| E-MTAB-5061 | yes | 6.41 |
Regulation
Is transcription factor: no
Upstream regulators (CollecTRI, top): MYC
miRNA regulators (miRDB)
44 targeting GPR4, 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-3148 | 99.97 | 75.06 | 6478 |
| HSA-MIR-4728-5P | 99.85 | 69.39 | 4718 |
| HSA-MIR-6785-5P | 99.82 | 68.68 | 4428 |
| HSA-MIR-323A-3P | 99.79 | 70.30 | 1739 |
| HSA-MIR-1299 | 99.77 | 71.24 | 2389 |
| HSA-MIR-1273H-5P | 99.77 | 66.32 | 2471 |
| HSA-MIR-3680-3P | 99.75 | 72.51 | 3095 |
| HSA-MIR-4306 | 99.72 | 70.50 | 3630 |
| HSA-MIR-149-3P | 99.72 | 68.22 | 3963 |
| HSA-MIR-4699-3P | 99.71 | 70.15 | 3142 |
| HSA-MIR-1283 | 99.69 | 72.42 | 3009 |
| HSA-MIR-6883-5P | 99.69 | 68.05 | 3785 |
| HSA-MIR-587 | 99.64 | 70.86 | 2611 |
| HSA-MIR-548AV-5P | 99.60 | 70.84 | 2107 |
| HSA-MIR-548K | 99.60 | 70.84 | 2107 |
| HSA-MIR-4261 | 99.59 | 70.30 | 3415 |
| HSA-MIR-7106-5P | 99.53 | 67.47 | 3574 |
| HSA-MIR-5689 | 99.50 | 71.26 | 1154 |
| HSA-MIR-8054 | 99.48 | 70.81 | 2084 |
| HSA-MIR-519D-5P | 99.41 | 69.30 | 2057 |
| HSA-MIR-4284 | 99.36 | 65.25 | 1293 |
| HSA-MIR-3978 | 99.24 | 68.39 | 2201 |
| HSA-MIR-6799-5P | 99.14 | 65.72 | 2093 |
| HSA-MIR-485-5P | 99.10 | 64.78 | 1889 |
| HSA-MIR-6884-5P | 99.10 | 64.50 | 1987 |
| HSA-MIR-661 | 99.09 | 65.94 | 2062 |
| HSA-MIR-511-5P | 98.97 | 70.94 | 2268 |
| HSA-MIR-3154 | 98.94 | 66.55 | 1455 |
| HSA-MIR-4755-3P | 98.77 | 65.59 | 1915 |
| HSA-MIR-5187-5P | 98.54 | 67.94 | 952 |
Literature-anchored findings (GeneRIF, showing 27)
- Endogenous GPR4 in endothelial cells may be a potential G protein-coupled receptor by which LPC signals proinflammatory activities. (PMID:12805023)
- GPR4, a close relative of OGR1, also responds to pH changes, but elicits cyclic AMP formation (PMID:12955148)
- sphingosylphosphorylcholine and lysophosphatidic acid are not the ligands for GPR4 and that this receptor may constitutively inhibit ERK1/2 activation (PMID:14567679)
- GPR4 and TDAG8 overexpression in human tumors plays a role in driving or maintaining tumor formation (PMID:15221007)
- results identify sphingosylphosphorylcholine and its receptor, G protein-coupled receptor 4(GPR4), as critical regulators of the angiogenic potential of endothelial cells (PMID:15857892)
- GPR4 may play a critical role in the inflammatory responses activated by lysophosphatidylcholine (PMID:16461426)
- GPR4 in brain endothelial cells regulates monocyte transmigration. (PMID:17364894)
- lysophosphatidylcholine receptor G protein-coupled receptor 4 (GPK4) was expressed in YPEN-1 cells and triggered the cAMP/protein kinase A/cAMP response element-binding protein pathway, resulting in upregulation of adhesion molecules. (PMID:17437524)
- Previously postulated “ligand-independent” signaling of GPR4 is mediated through proton-sensing mechanisms. (PMID:17462861)
- The mutation of histidine residue at 79, 165, or 269 from the N-terminal of GPR4 to phenylalanine shifted the half-maximal effective concentration (EC(50)) of proton-induced signaling activities to the right, including cAMP accumulation. (PMID:20211729)
- acidosis/GPR4 signaling regulates endothelial cell adhesion mainly through the G(s)/cAMP/Epac pathway (PMID:22110680)
- The results suggested that GPR4 may play an important role in the development of epithelial ovarian carcinoma (EOC), and its overexpression might be required for the angiogenesis, tumor growth, and metastasis of EOC (PMID:23888957)
- GPR4 induces angiogenesis via GPR4-induced p38-mediated IL6, IL8 and VEGFA secretion at acidic extracellular pH in squamous cell carcinoma of the head and neck (PMID:27078157)
- Proton-sensing GPR4 signaling mediated the proton-induced inhibitory effects on the osteogenesis of BMSCs. YAP was the downstream effector of GPR4 signaling. Extracellular pH modulates the osteogenic responses of BMSCs by regulating the proton-sensing GPR4-YAP pathway. (PMID:27256071)
- it was demonstrated that GPR4 affects ECs by regulating Notch1, a function that may be important for physiological and pathological angiogenesis. (PMID:27279286)
- acidosis/GPR4-induced endoplasmic reticulum stress pathways in endothelial cells may regulate vascular growth and inflammatory response in the acidic microenvironment. (PMID:28134810)
- These results suggest that zOGR1, but not GPR4, is also a metal-sensing G-protein-coupled receptor in addition to a proton-sensing G-protein-coupled receptor, although not all metals that activate hOGR1 activated zOGR1. (PMID:28270026)
- GPR4 blockade attenuated renal injury after IR and reduced the cell apoptosis through the suppression of CHOP expression. (PMID:29089376)
- Results indicate that GPR4 is expressed by multiple neuronal populations and endothelium and that its pH sensitivity is affected by level of expression and l-lactic acid (LL). GPR4 antagonist NE 52-QQ57 blunts hypercapnic response to CO2 but this effect is absent under anaesthesia, possibly due to the inhibitory effect of LL on GPR4. (PMID:29894771)
- The expression of GPR4 is upregulated in colorectal cancer and is associated with shorter overall survival time in CRC patients. These findings reveal the novel roles of GPR4 in CRC progression and suggest GPR4 might be a new therapeutic target for CRC treatment. (PMID:31530502)
- Antagonism of GPR4 with NE 52-QQ57 and the Suppression of AGE-Induced Degradation of Type II Collagen in Human Chondrocytes. (PMID:32370492)
- Expression profiles of proton-sensing G-protein coupled receptors in common skin tumors. (PMID:32948783)
- Hypoxia-induced GPR4 suppresses trophoblast cell migration and proliferation through the MAPK signaling pathway. (PMID:33161135)
- The evolution and mechanism of GPCR proton sensing. (PMID:33478938)
- GPR4 in the pH-dependent migration of melanoma cells in the tumor microenvironment. (PMID:36562556)
- Acid-sensing receptor GPR4 plays a crucial role in lymphatic cancer metastasis. (PMID:38410865)
- The proton-sensing receptors TDAG8 and GPR4 are differentially expressed in human and mouse oligodendrocytes: Exploring their role in neuroinflammation and multiple sclerosis. (PMID:38527054)
Cross-species orthologs
4 orthologs
| Organism | Symbol | Gene ID |
|---|---|---|
| danio_rerio | gpr4 | ENSDARG00000079479 |
| mus_musculus | Gpr4 | ENSMUSG00000044317 |
| rattus_norvegicus | Gpr4 | ENSRNOG00000016362 |
| caenorhabditis_elegans | WBGENE00016570 |
Paralogs (16): P2RY10 (ENSG00000078589), GPR18 (ENSG00000125245), F2RL3 (ENSG00000127533), GPR55 (ENSG00000135898), LPAR6 (ENSG00000139679), GPR65 (ENSG00000140030), GPR17 (ENSG00000144230), LPAR4 (ENSG00000147145), CYSLTR2 (ENSG00000152207), F2RL2 (ENSG00000164220), F2RL1 (ENSG00000164251), CYSLTR1 (ENSG00000173198), GPR35 (ENSG00000178623), F2R (ENSG00000181104), P2RY8 (ENSG00000182162), GPR20 (ENSG00000204882)
Protein
Protein identifiers
G-protein coupled receptor 4 — P46093 (reviewed: P46093)
Alternative names: G-protein coupled receptor 6C.l
All UniProt accessions (1): P46093
UniProt curated annotations — full annotation on UniProt →
Function. Proton-sensing G-protein coupled receptor activated by extracellular pH, which is required to monitor pH changes and generate adaptive reactions. Activated by an optimal pH of 6.8-7.2. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase. GPR4 is mainly coupled to G(s) G proteins and mediates activation of adenylate cyclase activity. May also couple with G(i), G(q) and G(12)/G(13) G proteins. Acts as a key regulator of respiratory sensitivity to CO2/H(+) in brain retrotrapezoid nucleus neurons: acts by mediating detection of protons generated by the formation of carbonic acid in the blood, an important mechanism to impulse to breathe. Also acts as a regulator of acid secretion in the kidney collecting duct by maintaining acid-base homeostasis in the kidney. Acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells, possibly through the G(12)/G(13)/Rho GTPase signaling pathway.
Subcellular location. Cell membrane.
Activity regulation. Activated by a network of residues that connects an extracellular-facing cavity to Glu-145, a conserved charged residue buried in the transmembrane core of the receptor. Protonation likely drives conformational changes in extracellular loop 2 (ECL2), which stabilizes movement of transmembrane 3 (TM3) and a series of rearrangements that connect the extracellular-facing cavity to Glu-145, a residue only conserved in proton-sensing G-protein coupled receptors. Inhibited by the antagonist NE52-QQ57, which prevents activation by protons.
Domain organisation. A multitude of proton-sensing residues, which include extracellular histidine residues (His-155, His-165 and His-269) or triad of buried acidic residues (Asp-63, Glu-145 and Asp-282), contribute to activation of the G-protein coupled receptor activity and pH sensitivity.
Similarity. Belongs to the G-protein coupled receptor 1 family.
RefSeq proteins (1): NP_005273* (*=MANE)
Domains & families (InterPro)
| ID | Name | Type |
|---|---|---|
| IPR000276 | GPCR_Rhodpsn | Family |
| IPR002276 | GPR4_orph | Family |
| IPR017452 | GPCR_Rhodpsn_7TM | Domain |
Pfam: PF00001
UniProt features (88 total): mutagenesis site 37, helix 13, topological domain 8, transmembrane region 7, sequence conflict 5, site 4, turn 3, strand 3, region of interest 2, glycosylation site 2, disulfide bond 2, chain 1, sequence variant 1
Structure
Experimental structures (PDB)
25 structures.
| PDB | Method | Resolution (Å) |
|---|---|---|
| 9JCO | ELECTRON MICROSCOPY | 2.36 |
| 8Z9O | ELECTRON MICROSCOPY | 2.4 |
| 8Z9P | ELECTRON MICROSCOPY | 2.5 |
| 9JCP | ELECTRON MICROSCOPY | 2.55 |
| 9JCQ | ELECTRON MICROSCOPY | 2.59 |
| 9LMP | ELECTRON MICROSCOPY | 2.65 |
| 9JFV | ELECTRON MICROSCOPY | 2.67 |
| 9IV6 | ELECTRON MICROSCOPY | 2.71 |
| 8Z3Q | ELECTRON MICROSCOPY | 2.76 |
| 9BIP | ELECTRON MICROSCOPY | 2.8 |
| 9LGM | ELECTRON MICROSCOPY | 2.84 |
| 9JFX | ELECTRON MICROSCOPY | 2.87 |
| 8Z3M | ELECTRON MICROSCOPY | 2.9 |
| 8ZCF | ELECTRON MICROSCOPY | 2.9 |
| 9JFZ | ELECTRON MICROSCOPY | 2.9 |
| 8Z65 | ELECTRON MICROSCOPY | 2.97 |
| 8Z66 | ELECTRON MICROSCOPY | 3.06 |
| 8ZCE | ELECTRON MICROSCOPY | 3.1 |
| 9JFW | ELECTRON MICROSCOPY | 3.13 |
| 8Z3Y | ELECTRON MICROSCOPY | 3.2 |
| 8Z67 | ELECTRON MICROSCOPY | 3.2 |
| 9LMO | ELECTRON MICROSCOPY | 3.2 |
| 9JFU | ELECTRON MICROSCOPY | 3.23 |
| 9JHP | ELECTRON MICROSCOPY | 3.35 |
| 9U4J | ELECTRON MICROSCOPY | 3.4 |
Predicted structure (AlphaFold)
| Model | pLDDT | Fraction very-high |
|---|---|---|
| AF-P46093-F1 | 80.97 | 0.52 |
Antibody-complex structures (SAbDab): 16 — 8Z3M, 8Z3Q, 8Z3Y, 8Z65, 8Z9O, 8Z9P, 8ZCE, 8ZCF, 9BIP, 9IV6, 9JFW, 9JFX, 9JFZ, 9JHP, 9LGM, 9LMO
Functional residue map
Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.
Catalytic / active sites (4): 145 (required for activation); 155 (proton sensing); 165 (proton sensing); 269 (proton sensing)
Disulfide bonds (2): 9–258, 90–168
Glycosylation sites (2): 3, 164
Mutagenesis-validated functional residues (37):
| Position | Phenotype |
|---|---|
| 4 | no effect on ph-sensing activity. |
| 10 | no effect on ph-sensing activity. |
| 17 | no effect on ph-sensing activity. |
| 24 | reduced inhibition by antagonist ne52-qq57. |
| 45 | induces a shift of the optimal ph for activation. |
| 51 | induces a shift of the optimal ph for activation. |
| 63 | impaired ability to sense protons. |
| 73 | reduced inhibition by antagonist ne52-qq57. |
| 76 | reduced inhibition by antagonist ne52-qq57. |
| 77 | reduced inhibition by antagonist ne52-qq57. |
| 79 | decreased proton-induced g-protein coupled receptor signaling. |
| 79 | displays smaller camp, rho, plc responses to mildly alkaline to acidic ph of 7.1 but almost the same or higher responses |
| 80 | does not affect sensitivity to protons. |
| 80 | no effect on ph-sensing activity. |
| 85 | does not affect sensitivity to protons. |
| 85 | no effect on ph-sensing activity. |
| 100 | increased potency of protons. |
| 115 | decreased proton-induced g-protein coupled receptor activity. endothelial permeability is decreased under acid condition |
| 129 | induces a shift of the optimal ph for activation. |
| 145 | mimics the protonation state; induces a shift of the optimal ph for activation. |
| 155 | does not affect sensitivity to protons. |
| 156 | increased basal activity and proton potencies. |
| 161 | decreased proton-induced g-protein coupled receptor signaling. |
| 162 | increased basal activity and proton potencies. |
| 165 | decreased proton-induced g-protein coupled receptor signaling. |
Function
Pathways and Gene Ontology
Reactome pathways
2 pathways
| ID | Pathway |
|---|---|
| R-HSA-373076 | Class A/1 (Rhodopsin-like receptors) |
| R-HSA-416476 | G alpha (q) signalling events |
MSigDB gene sets: 149 (showing top):
GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_EPITHELIAL_CELL_DEVELOPMENT, LFA1_Q6, GOBP_POSITIVE_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_WOUND_HEALING, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_CELL_DIFFERENTIATION_INVOLVED_IN_KIDNEY_DEVELOPMENT, BLALOCK_ALZHEIMERS_DISEASE_UP
GO Biological Process (13): G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), response to acidic pH (GO:0010447), negative regulation of angiogenesis (GO:0016525), regulation of cell adhesion (GO:0030155), positive regulation of Rho protein signal transduction (GO:0035025), regulation of vascular permeability (GO:0043114), positive regulation of inflammatory response (GO:0050729), angiogenesis involved in wound healing (GO:0060055), cellular response to acidic pH (GO:0071468), glomerular mesangial cell development (GO:0072144), signal transduction (GO:0007165)
GO Molecular Function (1): G protein-coupled receptor activity (GO:0004930)
GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)
Reactome top-level categories
Rollup of top-2 pathways:
| Category | Pathways |
|---|---|
| GPCR ligand binding | 1 |
| GPCR downstream signalling | 1 |
GO top-level categories
Rollup of top GO terms by namespace:
| Category | Terms |
|---|---|
| G protein-coupled receptor signaling pathway | 2 |
| angiogenesis | 2 |
| regulation of cellular process | 2 |
| G protein-coupled receptor activity | 1 |
| signal transduction | 1 |
| adenylate cyclase-modulating G protein-coupled receptor signaling pathway | 1 |
| adenylate cyclase activator activity | 1 |
| phospholipase C activator activity | 1 |
| response to pH | 1 |
| regulation of angiogenesis | 1 |
| negative regulation of blood vessel morphogenesis | 1 |
| cell adhesion | 1 |
| Rho protein signal transduction | 1 |
| regulation of Rho protein signal transduction | 1 |
| positive regulation of small GTPase mediated signal transduction | 1 |
| vascular process in circulatory system | 1 |
| blood circulation | 1 |
| regulation of biological quality | 1 |
| inflammatory response | 1 |
| positive regulation of defense response | 1 |
| positive regulation of response to external stimulus | 1 |
| regulation of inflammatory response | 1 |
| wound healing | 1 |
| response to acidic pH | 1 |
| cellular response to pH | 1 |
| epithelial cell development | 1 |
| glomerular mesangial cell differentiation | 1 |
| mesangial cell development | 1 |
| cell communication | 1 |
| cellular process | 1 |
| signaling | 1 |
| cellular response to stimulus | 1 |
| transmembrane signaling receptor activity | 1 |
| membrane | 1 |
| cell periphery | 1 |
| cellular anatomical structure | 1 |
Protein interactions and networks
STRING
768 interactions, top by confidence (×1000):
| Protein A | Protein B | Partner UniProt | Score |
|---|---|---|---|
| GPR4 | MAP3K4 | Q9Y6R4 | 760 |
| GPR4 | LPAR1 | P78351 | 691 |
| GPR4 | CGA | P01215 | 674 |
| GPR4 | KCNK5 | O95279 | 577 |
| GPR4 | GPR3 | P46089 | 553 |
| GPR4 | PHOX2B | Q99453 | 527 |
| GPR4 | GPR88 | Q9GZN0 | 526 |
| GPR4 | RAMP3 | O60896 | 497 |
| GPR4 | NDP | Q00604 | 491 |
| GPR4 | LGR4 | Q9BXB1 | 484 |
| GPR4 | RSPO1 | Q2MKA7 | 481 |
| GPR4 | GPR12 | P47775 | 466 |
| GPR4 | ASIC3 | Q9UHC3 | 449 |
| GPR4 | GPR132 | Q9UNW8 | 446 |
| GPR4 | GPR6 | P46095 | 426 |
IntAct
6 interactions, top by confidence:
| A | B | Type | Score |
|---|---|---|---|
| GPR4 | RAMP1 | psi-mi:“MI:0915”(physical association) | 0.400 |
| GPR4 | RAMP2 | psi-mi:“MI:0915”(physical association) | 0.400 |
| RAMP2 | GPR4 | psi-mi:“MI:0915”(physical association) | 0.400 |
| RAMP3 | GPR4 | psi-mi:“MI:0915”(physical association) | 0.400 |
| GPR4 | RAMP3 | psi-mi:“MI:0915”(physical association) | 0.400 |
BioGRID (6): GPR4 (Affinity Capture-MS), GPR4 (Affinity Capture-Western), GPRASP1 (Affinity Capture-Western), RABGEF1 (Affinity Capture-Western), STAM (Affinity Capture-Western), VPS28 (Affinity Capture-Western)
ESM2 similar proteins: A0A4W3GG95, A7YY44, B0F9W3, B0UXR0, B2GV46, B3G515, B5X337, E7FEL0, O00398, O46685, O70526, P21556, P25023, P25105, P25116, P26824, P30411, P30558, P32299, P43657, P46002, P46093, P49019, P50132, P56488, Q00991, Q15743, Q1JQB3, Q28642, Q3UFD7, Q4G072, Q4KLH9, Q61038, Q62035, Q80Z39, Q8BFQ3, Q8BFU7, Q8BLG2, Q8BMC0, Q8BUD0
Diamond homologs: A0A4W3GG95, A0A6I8PUB9, A6QLE7, D4A7K7, E7FEL0, E9QJ73, O00254, O08675, O46685, P0C0W8, P0C5J4, P32246, P32249, P32250, P34996, P35366, P35383, P41231, P41232, P46093, P47900, P48042, P49650, P49651, P49652, P50132, P56482, P58826, P59902, P79928, P97266, Q149R9, Q15743, Q1JQB3, Q2Y2P0, Q3U6B2, Q3ZC80, Q4G072, Q4KLH9, Q5E9H8
SIGNOR signaling
0 interactions.
Disease & clinical
Clinical variants and AI predictions
ClinVar
44 variants total. Per-class counts are floors (≥ shown; pagination cap):
| Classification | Count (floor) |
|---|---|
| Pathogenic | 0 |
| Likely pathogenic | 0 |
| Uncertain significance | 42 |
| Likely benign | 1 |
| Benign | 0 |
Top pathogenic / likely-pathogenic (0)
SpliceAI
362 predictions. Top by Δscore:
| Variant | Effect | Δscore |
|---|---|---|
| 19:45602091:TTA:T | donor_loss | 1.0000 |
| 19:45602093:A:AC | donor_gain | 1.0000 |
| 19:45602093:AC:A | donor_gain | 1.0000 |
| 19:45602093:ACCTG:A | donor_gain | 1.0000 |
| 19:45602094:C:CG | donor_gain | 1.0000 |
| 19:45602094:CC:C | donor_gain | 1.0000 |
| 19:45602094:CCT:C | donor_gain | 1.0000 |
| 19:45602094:CCTG:C | donor_gain | 1.0000 |
| 19:45602094:CCTGC:C | donor_gain | 1.0000 |
| 19:45592643:T:TA | donor_gain | 0.8800 |
| 19:45591795:G:C | acceptor_gain | 0.8400 |
| 19:45592634:C:CA | donor_gain | 0.7800 |
| 19:45592909:AGG:A | donor_gain | 0.7800 |
| 19:45591793:A:C | acceptor_gain | 0.7300 |
| 19:45592634:CCAG:C | donor_gain | 0.7200 |
| 19:45591793:A:AC | acceptor_gain | 0.7100 |
| 19:45602090:CTTA:C | donor_gain | 0.7000 |
| 19:45602093:ACC:A | donor_gain | 0.6800 |
| 19:45593193:GTCT:G | acceptor_gain | 0.6700 |
| 19:45602091:TTACC:T | donor_gain | 0.6700 |
| 19:45602092:TACCT:T | donor_gain | 0.6700 |
| 19:45593194:TCTC:T | acceptor_gain | 0.6600 |
| 19:45592638:A:AC | donor_gain | 0.6500 |
| 19:45592639:C:CC | donor_gain | 0.6500 |
| 19:45600526:AC:A | donor_gain | 0.6400 |
| 19:45600527:CC:C | donor_gain | 0.6400 |
| 19:45591795:G:GC | acceptor_gain | 0.6100 |
| 19:45591783:G:T | acceptor_gain | 0.6000 |
| 19:45602089:ACTT:A | donor_gain | 0.6000 |
| 19:45592693:AGTGC:A | acceptor_loss | 0.5800 |
AlphaMissense
2358 scored. Top likely-pathogenic:
| Variant | Protein change | am_pathogenicity |
|---|---|---|
| 19:45591618:C:A | W83C | 1.000 |
| 19:45591618:C:G | W83C | 1.000 |
| 19:45591039:G:C | S276R | 0.999 |
| 19:45591039:G:T | S276R | 0.999 |
| 19:45591041:T:G | S276R | 0.999 |
| 19:45591156:A:C | F237L | 0.999 |
| 19:45591156:A:T | F237L | 0.999 |
| 19:45591158:A:G | F237L | 0.999 |
| 19:45591363:G:C | C168W | 0.999 |
| 19:45591364:C:G | C168S | 0.999 |
| 19:45591364:C:T | C168Y | 0.999 |
| 19:45591365:A:G | C168R | 0.999 |
| 19:45591365:A:T | C168S | 0.999 |
| 19:45591443:A:G | W142R | 0.999 |
| 19:45591443:A:T | W142R | 0.999 |
| 19:45591453:G:C | S138R | 0.999 |
| 19:45591453:G:T | S138R | 0.999 |
| 19:45591455:T:G | S138R | 0.999 |
| 19:45591555:G:C | S104R | 0.999 |
| 19:45591555:G:T | S104R | 0.999 |
| 19:45591557:T:G | S104R | 0.999 |
| 19:45591567:A:C | N100K | 0.999 |
| 19:45591567:A:T | N100K | 0.999 |
| 19:45591598:C:G | C90S | 0.999 |
| 19:45591598:C:T | C90Y | 0.999 |
| 19:45591599:A:T | C90S | 0.999 |
| 19:45591620:A:G | W83R | 0.999 |
| 19:45591620:A:T | W83R | 0.999 |
| 19:45591679:T:G | D63A | 0.999 |
| 19:45591691:A:G | L59P | 0.999 |
dbSNP variants (sampled 300 via entrez): RS1000116765 (19:45602359 T>G), RS1000314680 (19:45591220 C>A,T), RS1000475905 (19:45598113 C>T), RS1000487173 (19:45602778 C>CT), RS1000590080 (19:45597853 T>A), RS1001168085 (19:45597498 G>A), RS1001654435 (19:45599976 C>G,T), RS1001798079 (19:45602939 C>T), RS1001852159 (19:45602725 G>T), RS1001887655 (19:45590113 CATA>C), RS1002143070 (19:45597561 C>G,T), RS1002337970 (19:45596519 A>G), RS1002341632 (19:45589831 C>T), RS1002472002 (19:45600141 G>A,C,T), RS1002493965 (19:45597262 T>C)
Disease associations
OMIM: gene MIM:600551 | disease phenotypes:
GenCC curated gene-disease
Mondo (0):
Orphanet (0):
HPO phenotypes
0 total (0 of 0 shown, HPO-id order):
GWAS associations
0 associations (top):
Drugs & pharmacology
Drug and pharmacology data
Is drug target: yes
ChEMBL targets (1): CHEMBL3638324 (SINGLE PROTEIN)
PharmGKB: 1 entry (VIP=true, CPIC=false)
GtoPdb / IUPHAR curated pharmacology
(IUPHAR/BPS Guide to Pharmacology — expert-curated)
Target class: gpcr — Class A Orphans with emerging pharmacology
Most potent curated ligand interactions (2 total), top 2:
| Ligand | Action | Affinity | Parameter |
|---|---|---|---|
| GPR4 antagonist 3b | Antagonist | 7.17 | pIC50 |
| NE 52-QQ57 | Antagonist | 7.15 | pIC50 |
Binding affinities (BindingDB)
37 measured of 37 human assays (37 total across all organisms); most potent 37 below. Values come from heterogeneous assays and are not directly comparable.
| Ligand | Measure | Value | Patent |
|---|---|---|---|
| 4-[5-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]-1,3,4-oxadiazol-2-yl]cyclohexan-1-amine | IC50 | 5 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 1-[(2S)-4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]-1-methylpiperazin-2-yl]-N,N-dimethylmethanamine | IC50 | 7 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-ethyl-5,7-dimethyl-3-[[4-[(E)-3-piperazin-1-ylprop-1-enyl]phenyl]methyl]pyrazolo[1,5-a]pyrimidine | IC50 | 10 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-ethyl-5,7-dimethyl-3-[[4-[3-(4-propan-2-ylpiperazin-1-yl)propyl]phenyl]methyl]pyrazolo[1,5-a]pyrimidine | IC50 | 13 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| (2S,4S)-4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]-2-methylpiperidin-4-ol | IC50 | 15 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| (2S)-1-[4-[5-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]-1,3,4-oxadiazol-2-yl]piperidin-1-yl]-3-hydroxy-2-(methylamino)propan-1-one | IC50 | 15 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-ethyl-5,7-dimethyl-3-[[4-[(E)-3-[(3S)-3-methylpiperazin-1-yl]prop-1-enyl]phenyl]methyl]pyrazolo[1,5-a]pyrimidine | IC50 | 19 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| [4-[[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenoxy]methyl]piperidin-1-yl]-[(2S,3R)-3-hydroxypyrrolidin-2-yl]methanone | IC50 | 19 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 1-[[1-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]pyrazol-4-yl]methyl]azetidin-3-amine | IC50 | 21 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-ethyl-5,7-dimethyl-3-[[4-(piperidin-4-ylmethoxy)phenyl]methyl]pyrazolo[1,5-a]pyrimidine | IC50 | 22 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| (2R)-3-[4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]-4-hydroxypiperidin-1-yl]propane-1,2-diol | IC50 | 24 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 1-[[1-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]pyrazol-4-yl]methyl]piperidin-4-amine | IC50 | 26 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| [(2S)-4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]piperazin-2-yl]methanol | IC50 | 28 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| (2R)-1-[tert-butyl(dimethyl)silyl]oxy-3-[4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]piperazin-1-yl]propan-2-ol | IC50 | 30 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-ethyl-3-[[4-[(E)-3-[(3S)-3-(methoxymethyl)piperazin-1-yl]prop-1-enyl]phenyl]methyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine | IC50 | 33 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-ethyl-5,7-dimethyl-3-[[4-[(E)-3-[4-(1-methyltetrazol-5-yl)piperidin-1-yl]prop-1-enyl]phenyl]methyl]pyrazolo[1,5-a]pyrimidine | IC50 | 33 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| tert-butyl 3-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]-3-hydroxyazetidine-1-carboxylate | IC50 | 34 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| tert-butyl N-[2-[4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]-4-hydroxypiperidin-1-yl]-2-oxoethyl]-N-methylcarbamate | IC50 | 34 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| [4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]piperazin-1-yl]-[(2S,3R)-3-hydroxypyrrolidin-2-yl]methanone | IC50 | 35 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 4-[[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenoxy]methyl]cyclohexan-1-amine | IC50 | 35 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-amino-1-[4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]piperazin-1-yl]ethanone | IC50 | 38 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-ethyl-5,7-dimethyl-3-[[4-[4-(piperazin-1-ylmethyl)triazol-1-yl]phenyl]methyl]pyrazolo[1,5-a]pyrimidine | IC50 | 38 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-ethyl-5,7-dimethyl-3-[[4-[4-(piperazin-1-ylmethyl)pyrazol-1-yl]phenyl]methyl]pyrazolo[1,5-a]pyrimidine | IC50 | 43 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]piperidin-4-ol | IC50 | 44 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| tert-butyl 4-[2-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenoxy]ethyl]piperazine-1-carboxylate | IC50 | 44 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| tert-butyl 4-[(E)-2-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]ethenyl]-4-hydroxypiperidine-1-carboxylate | IC50 | 45 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| tert-butyl 4-[3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]propyl]-4-hydroxypiperidine-1-carboxylate | IC50 | 47 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| (2S)-1-[4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]piperazin-1-yl]-3-hydroxy-2-(methylamino)propan-1-one | IC50 | 51 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| tert-butyl 4-[3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]propanoyl]piperazine-1-carboxylate | IC50 | 54 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| (2S,3R)-N-[4-[[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenoxy]methyl]cyclohexyl]-3-hydroxypyrrolidine-2-carboxamide | IC50 | 54 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-ethyl-5,7-dimethyl-3-[[4-[(E)-3-(4-propan-2-ylpiperazin-1-yl)prop-1-enyl]phenyl]methyl]imidazo[4,5-b]pyridine | IC50 | 55 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-ethyl-3-[[4-[2-[(3R)-3-(methoxymethyl)piperazin-1-yl]ethoxy]phenyl]methyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine | IC50 | 59 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 2-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]-5-piperidin-4-yl-1,3,4-oxadiazole | IC50 | 74 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| tert-butyl 4-[[1-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]triazol-4-yl]methyl]-4-hydroxypiperidine-1-carboxylate | IC50 | 77 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| (E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]-1-(4-methylpiperazin-1-yl)prop-2-en-1-one | IC50 | 81 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 4-[2-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenoxy]ethyl]piperidin-4-ol | IC50 | 110 nM | US-8748435: Pyrazolo pyrimidine derivatives |
| 1-[[1-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]pyrazol-4-yl]methyl]azetidin-3-ol | IC50 | 118 nM | US-8748435: Pyrazolo pyrimidine derivatives |
ChEMBL bioactivities
78 potent at pChembl≥5 of 79 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).
PubChem BioAssay actives
41 with measured affinity, of 78 total; 37 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 |
|---|---|---|---|---|
| 2-ethyl-5,7-dimethyl-3-[[4-[3-(4-propan-2-ylpiperazin-1-yl)propyl]phenyl]methyl]pyrazolo[1,5-a]pyrimidine | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.0200 | uM |
| (2R)-3-[4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]piperazin-1-yl]propane-1,2-diol | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.0210 | uM |
| 3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]-1-piperidin-4-ylpropan-1-ol | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.0240 | uM |
| 4-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]piperazin-2-one | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.0270 | uM |
| 2-ethyl-5,7-dimethyl-3-[[4-[(E)-3-(4-propan-2-ylpiperazin-1-yl)prop-1-enyl]phenyl]methyl]pyrazolo[1,5-a]pyrimidine | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.0430 | uM |
| 1-[2-[1-[4-[[2,2-dimethylpropyl-(2,6-dimethylpyrimidin-4-yl)amino]methyl]phenyl]triazol-4-yl]ethyl]piperidin-4-ol | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.0500 | uM |
| 4-[3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]propyl]piperidin-4-ol | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.0500 | uM |
| 3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]-1-piperazin-1-ylpropan-1-one | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.0530 | uM |
| 4-[3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]propyl]-1-propan-2-ylpiperidin-4-ol | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.0630 | uM |
| 3-[(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-yl)methyl]-8-(piperidin-1-ylmethyl)-6,11-dihydro-5H-benzo[b][1]benzazepine | 1304136: Antagonist activity at N-terminal HA-tagged GPR4 (unknown origin) expressed in HEK293 cells assessed as inhibition of pH dependent cAMP response element-driven transcriptional activity at pH 7.2 incubated for 6 hrs by dual luciferase reporter gene assay | ic50 | 0.0670 | uM |
| 2-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]-5-piperidin-4-yl-1,3,4-oxadiazole | 1364859: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins in presence of 40% rat plasma by HTRF assay | ic50 | 0.0670 | uM |
| 1-[(E)-3-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]prop-2-enyl]piperazin-2-one | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.0730 | uM |
| 2-ethyl-6,8-dimethyl-3-[[4-[(E)-3-(4-propan-2-ylpiperazin-1-yl)prop-1-enyl]phenyl]methyl]imidazo[1,2-b]pyridazine | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.0740 | uM |
| 2-ethyl-5,7-dimethyl-3-[[4-[(E)-3-(4-propan-2-ylpiperazin-1-yl)prop-1-enyl]phenyl]methyl]imidazo[4,5-b]pyridine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.1100 | uM |
| 3-[(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-yl)methyl]-8-[(4-methylpiperazin-1-yl)methyl]-6,11-dihydro-5H-benzo[b][1]benzazepine | 1304136: Antagonist activity at N-terminal HA-tagged GPR4 (unknown origin) expressed in HEK293 cells assessed as inhibition of pH dependent cAMP response element-driven transcriptional activity at pH 7.2 incubated for 6 hrs by dual luciferase reporter gene assay | ic50 | 0.1300 | uM |
| N-(2,2-dimethylpropyl)-2-methoxy-N-[[4-[3-(4-propan-2-ylpiperazin-1-yl)prop-1-ynyl]phenyl]methyl]pyrimidin-4-amine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.1400 | uM |
| N-[4-(dimethylamino)butyl]-4-[[2,2-dimethylpropyl-(2,6-dimethylpyrimidin-4-yl)amino]methyl]benzamide | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.1600 | uM |
| 5-(dimethylamino)-N-[4-[[2,2-dimethylpropyl-(2,6-dimethylpyrimidin-4-yl)amino]methyl]phenyl]pentanamide | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.2000 | uM |
| 2-chloro-N-(2,2-dimethylpropyl)-N-[[4-[3-(4-propan-2-ylpiperazin-1-yl)prop-1-ynyl]phenyl]methyl]pyrimidin-4-amine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.3000 | uM |
| N-(2,2-dimethylpropyl)-2,6-dimethyl-N-[[4-[(E)-3-(4-propan-2-ylpiperazin-1-yl)prop-1-enyl]phenyl]methyl]pyrimidin-4-amine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.3300 | uM |
| 2-chloro-N-(2,2-dimethylpropyl)-N-[[4-[(E)-3-(4-piperidin-1-ylpiperidin-1-yl)prop-1-enyl]phenyl]methyl]pyrimidin-4-amine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.3600 | uM |
| 2-[4-[(2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]phenyl]-5-piperazin-1-yl-1,3,4-oxadiazole | 1364843: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of IBMX-induced cAMP accumulation after 15 mins by HTRF assay | ic50 | 0.3680 | uM |
| N-(2,2-dimethylpropyl)-2-methyl-N-[[4-[(E)-3-(4-piperidin-1-ylpiperidin-1-yl)prop-1-enyl]phenyl]methyl]pyrimidin-4-amine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.3800 | uM |
| N-(2,2-dimethylpropyl)-2,6-dimethyl-N-[[4-[(E)-3-(4-piperidin-1-ylpiperidin-1-yl)prop-1-enyl]phenyl]methyl]pyrimidin-4-amine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.4100 | uM |
| 2,5,7-trimethyl-3-[[4-[(E)-3-(4-propan-2-ylpiperazin-1-yl)prop-1-enyl]phenyl]methyl]imidazo[4,5-b]pyridine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.4100 | uM |
| 4-[2,2-dimethylpropyl-[[4-[(E)-3-(4-piperidin-1-ylpiperidin-1-yl)prop-1-enyl]phenyl]methyl]amino]pyrimidine-2-carbonitrile | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.4900 | uM |
| N-(2,2-dimethylpropyl)-2-methoxy-N-[[4-[(E)-3-(4-piperidin-1-ylpiperidin-1-yl)prop-1-enyl]phenyl]methyl]pyrimidin-4-amine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.7000 | uM |
| 5,7-dimethyl-3-[[4-[(E)-3-(4-propan-2-ylpiperazin-1-yl)prop-1-enyl]phenyl]methyl]-2-propylimidazo[4,5-b]pyridine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.7600 | uM |
| N-(2,2-dimethylpropyl)-2,6-dimethyl-N-[[4-[3-(4-propan-2-ylpiperazin-1-yl)prop-1-ynyl]phenyl]methyl]pyrimidin-4-amine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 0.8000 | uM |
| 3-[(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-yl)methyl]-6,11-dihydro-5H-benzo[b][1]benzazepine | 1304136: Antagonist activity at N-terminal HA-tagged GPR4 (unknown origin) expressed in HEK293 cells assessed as inhibition of pH dependent cAMP response element-driven transcriptional activity at pH 7.2 incubated for 6 hrs by dual luciferase reporter gene assay | ic50 | 0.9000 | uM |
| 3-[(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-yl)methyl]-10H-phenothiazine | 1304136: Antagonist activity at N-terminal HA-tagged GPR4 (unknown origin) expressed in HEK293 cells assessed as inhibition of pH dependent cAMP response element-driven transcriptional activity at pH 7.2 incubated for 6 hrs by dual luciferase reporter gene assay | ic50 | 0.9100 | uM |
| 4-[2,2-dimethylpropyl-[[4-[3-(4-propan-2-ylpiperazin-1-yl)prop-1-ynyl]phenyl]methyl]amino]pyrimidine-2-carbonitrile | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 1.9300 | uM |
| 5,7-dimethyl-2-propan-2-yl-3-[[4-[(E)-3-(4-propan-2-ylpiperazin-1-yl)prop-1-enyl]phenyl]methyl]imidazo[4,5-b]pyridine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 2.4400 | uM |
| N-(2,2-dimethylpropyl)-N-[[4-[(E)-3-(4-piperidin-1-ylpiperidin-1-yl)prop-1-enyl]phenyl]methyl]-6-(trifluoromethyl)pyrimidin-4-amine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 2.9700 | uM |
| 4-N-(2,2-dimethylpropyl)-2-N,2-N-dimethyl-4-N-[[4-[(E)-3-(4-piperidin-1-ylpiperidin-1-yl)prop-1-enyl]phenyl]methyl]pyrimidine-2,4-diamine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 4.8000 | uM |
| 5,7-dimethyl-2-(2-methylpropyl)-3-[[4-[(E)-3-(4-propan-2-ylpiperazin-1-yl)prop-1-enyl]phenyl]methyl]imidazo[4,5-b]pyridine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 7.3100 | uM |
| 2-ethyl-3-[[4-[(E)-3-(4-propan-2-ylpiperazin-1-yl)prop-1-enyl]phenyl]methyl]imidazo[4,5-b]pyridine | 1461629: Antagonist activity at human GPR4 expressed in human HeLa cells assessed as inhibition of pH-induced cAMP accumulation preincubated for 15 mins followed by cAMP addition measured after 60 mins by HTRF method | ic50 | 9.1000 | uM |
CTD chemical–gene interactions
25 total (human), top 25 by PubMed support.
| Chemical | Actions (top 5) | PubMed papers |
|---|---|---|
| Acetaminophen | decreases expression, increases expression | 2 |
| Benzo(a)pyrene | increases methylation, affects methylation, decreases expression | 2 |
| Valproic Acid | affects expression, increases methylation | 2 |
| bisphenol A | decreases expression | 1 |
| quercitrin | increases expression | 1 |
| sodium arsenite | increases expression | 1 |
| cobaltous chloride | decreases expression | 1 |
| butyraldehyde | increases expression | 1 |
| cupric chloride | increases expression | 1 |
| nickel sulfate | decreases expression | 1 |
| perfluorooctane sulfonic acid | increases expression | 1 |
| SCH772984 | affects phosphorylation, decreases reaction | 1 |
| Sugars | affects binding, decreases activity, decreases reaction, increases expression | 1 |
| Anti-Inflammatory Agents | affects binding, decreases activity, decreases reaction, increases expression | 1 |
| Biological Factors | affects binding, decreases activity, decreases reaction, increases expression | 1 |
| Cadmium | decreases expression | 1 |
| Estradiol | increases expression, affects cotreatment | 1 |
| Lysophosphatidylcholines | increases expression, increases reaction | 1 |
| Methotrexate | decreases expression | 1 |
| Nickel | increases expression | 1 |
| Oxygen | increases expression | 1 |
| Smoke | decreases expression | 1 |
| Antirheumatic Agents | decreases expression | 1 |
| Cadmium Chloride | increases expression | 1 |
| tert-Butylhydroperoxide | increases expression | 1 |
ChEMBL screening assays
15 unique, capped per target: 10 functional, 5 binding
Representative assays (with source publication via chembl_document):
| Assay ID | Type | Description | Source paper |
|---|---|---|---|
| CHEMBL3705172 | Binding | Radio Ligand Binding Assay: Serial dilutions of compounds (stock in 10 mM DMSO) are prepared by first diluting the compounds in DMSO followed by a 1:50 dilution into assay buffer (10 mM HEPES, pH 8.0, 100 mM NaCl, 5 mM MgCl2, 1 mM CaCl2, 0. | Pyrazolo pyrimidine derivatives |
| CHEMBL3734137 | Functional | Antagonist activity at human GPR4 expressed in KJMGER8 cells assessed as inhibition of 17beta-estradiol-induced response after 6 hrs by steady glo luciferase reporter assay | Preventive and/or therapeutic agent for neutrophilic inflammatory diseases |
Cellosaurus cell lines
1 cell lines: 1 spontaneously immortalized cell line
First 10 cell lines (id-ordered, not curated):
| Cellosaurus | Name | Category | Sex |
|---|---|---|---|
| CVCL_KX63 | PathHunter CHO-K1 GPR4 beta-arrestin | Spontaneously immortalized cell line | Female |
Clinical trials (associated diseases)
0 trials via MONDO — disease-level, not drug-specific.
Related Atlas pages
No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.