GRM4

Summary

GRM4 (glutamate metabotropic receptor 4, HGNC:4596) is a protein-coding gene on chromosome 6p21.31, encoding Metabotropic glutamate receptor 4 (Q14833). G-protein coupled receptor for glutamate.

L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2914 — RefSeq curated summary.

At a glance

• GWAS associations: 32
• Clinical variants (ClinVar): 140 total
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000841

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4596
Approved symbol	GRM4
Name	glutamate metabotropic receptor 4
Location	6p21.31
Locus type	gene with protein product
Status	Approved
Aliases	GPRC1D, mGlu4, MGLUR4
Ensembl gene	ENSG00000124493
Ensembl biotype	protein_coding
OMIM	604100
Entrez	2914

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000374177, ENST00000374181, ENST00000455714, ENST00000535756, ENST00000538487, ENST00000544773, ENST00000545715, ENST00000607916, ENST00000609222, ENST00000609278, ENST00000609443, ENST00000609860, ENST00000609915, ENST00000609973, ENST00000936005, ENST00000936006, ENST00000936007, ENST00000936008, ENST00000936009, ENST00000936010, ENST00000936011

RefSeq mRNA: 6 — MANE Select: NM_000841 NM_000841, NM_001256809, NM_001256811, NM_001256812, NM_001256813, NM_001282847

CCDS: CCDS4787, CCDS59010, CCDS59011, CCDS59012, CCDS75432

Canonical transcript exons

ENST00000538487 — 11 exons

Exon	Start	End
ENSE00001106023	34091883	34092099
ENSE00001872928	34018643	34022870
ENSE00002232069	34132978	34133859
ENSE00002279234	34146000	34146087
ENSE00003483358	34058974	34059128
ENSE00003619576	34061893	34062028
ENSE00003702848	34056544	34056684
ENSE00003703128	34028120	34028366
ENSE00003704902	34040548	34040748
ENSE00003706085	34040178	34040314
ENSE00003709960	34035668	34036603

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 98.88.

FANTOM5 (CAGE): breadth broad, TPM avg 4.3750 / max 2085.6814, expressed in 320 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73214	3.7791	276
73211	0.3309	109
73212	0.0739	31
73215	0.0654	30
73213	0.0570	13
73206	0.0452	6
73216	0.0207	5
73207	0.0027	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
paraflocculus	UBERON:0005351	98.88	gold quality
cerebellar hemisphere	UBERON:0002245	98.44	gold quality
cerebellar cortex	UBERON:0002129	98.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.77	gold quality
cerebellum	UBERON:0002037	97.67	gold quality
endometrium epithelium	UBERON:0004811	94.97	silver quality
cerebellar vermis	UBERON:0004720	86.87	gold quality
tendon of biceps brachii	UBERON:0008188	85.87	silver quality
buccal mucosa cell	CL:0002336	84.91	silver quality
gluteal muscle	UBERON:0002000	84.20	gold quality
nucleus accumbens	UBERON:0001882	83.74	gold quality
putamen	UBERON:0001874	80.77	gold quality
caudate nucleus	UBERON:0001873	80.70	gold quality
Brodmann (1909) area 10	UBERON:0013541	80.55	silver quality
middle frontal gyrus	UBERON:0002702	80.24	silver quality
frontal pole	UBERON:0002795	78.50	gold quality
gingival epithelium	UBERON:0001949	76.68	gold quality
islet of Langerhans	UBERON:0000006	76.22	gold quality
periodontal ligament	UBERON:0008266	76.17	silver quality
quadriceps femoris	UBERON:0001377	75.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.61	gold quality
vastus lateralis	UBERON:0001379	75.61	gold quality
type B pancreatic cell	CL:0000169	74.83	gold quality
thymus	UBERON:0002370	74.63	silver quality
olfactory bulb	UBERON:0002264	74.53	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	74.43	gold quality
gingiva	UBERON:0001828	74.36	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	74.28	gold quality
pons	UBERON:0000988	73.96	gold quality
parotid gland	UBERON:0001831	73.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

159 targeting GRM4, 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-4673	100.00	66.64	1490
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4492	99.87	68.25	3611

Literature-anchored findings (GeneRIF, showing 23)

• residues shaping the binding pocket determine ligand selectivity for mGLUR4 (PMID:15184361)
• mGluR4 has a role in 5-FU resistance in colonic neoplasms (PMID:15217955)
• Results suggest that overexpression of mGluR4 is associated with poor prognosis. (PMID:15867225)
• mGluR4 internalization and desensitization are agonist-independent unless pathways leading to the activation of PKC are induced. (PMID:16582932)
• These data suggest that mGlu4 receptor enhancers are promising drugs for the treatment of medulloblastomas. (PMID:16899734)
• the effects of P-Ser (inhibition of neural stem cell proliferation and self-renewal, enhanced neurogenic fate commitment, and improved neuronal survival) are mediated bymGluR4. (PMID:17884634)
• GRM4 sequence variants might confer low-risk effects to the etiology of idiopathic generalized epilepsies. (PMID:20338729)
• Data show that mGlu2 and mGlu4 subunits (but not mGlu2 and mGlu1) can heteromerize. (PMID:20826542)
• study found that only one of the five SNPs tested showed a moderate but statistically significant association with juvenile myoclonic epilepsy in an Indian population (PMID:24840839)
• The major depression subjects exhibited significantly higher expression level in the metabotropic receptor genes GRM4 in Locus coeruleus neurons. (PMID:24925192)
• The GRM4 gene polymorphism was associated with the susceptibility and metastasis of osteosarcoma in a Chinese Han population. (PMID:24984297)
• explored the relationship between the binding pockets of mGlu4-positive allosteric modulators with different chemical scaffolds and their functional properties (PMID:25342125)
• Our data suggest that GRM4 gene polymorphism is closely related to the morbidity and metastasis of osteosarcoma in a Chinese population. (PMID:26276359)
• Results suggest that variant rs2229901 of glutamate receptor 4 is associated with major depressive disorder risk. This variant probably impacts the interaction between GRM4 and miR-1202. (PMID:27792966)
• EGR1 and CTCF are probably involved in the transcriptional regulation of GRM4, which participates in the progress of osteosarcoma by interacting with chemokines and their receptors. (PMID:29339716)
• We identified multiple novel associations of genetic variants in GRM3, GRM4, and GRM5 with the risk and the survival of renal cell carcinoma (RCC). These relationships were supported by gene expression profiles obtained using bioinformatics analysis. Specifically, the expression of GRM4 and GRM5 showed an increasing trend in RCC tissues, compared to that in normal tissue, whereas GRM3 was downregulated in RCC. (PMID:30488581)
• Results supply an important evidence that mGluR4 is expressed in prenatal human cerebrum, and main kinds of cells related to neurogenesis are involved in its expression. (PMID:30954358)
• Ectopic expression of glutamate metabotropic receptors (GRM) is correlated with better prognosis of breast cancer (BC)patients. Overexpression of GRM4 significantly inhibits cell proliferation, migration and invasion capacity in BC cell line MDA-MB-231. Overexpression of miR-328-3p and miR-370-3p counteracts the inhibitory effect of GRM4-induced cell proliferation, migration and invasion. (PMID:31492116)
• Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23. (PMID:31527131)
• This is the evidence supporting the interaction between GRM4 and CBX4, which could inhibit the malignant behavior of osteosarcoma cells through the GRM4/CBX4/HIF-1alpha signaling pathway (PMID:31581881)
• Association between the group III metabotropic glutamate receptor gene polymorphisms and attention-deficit/hyperactivity disorder and functional exploration of risk loci. (PMID:33068816)
• Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4. (PMID:34135510)
• Regulation and functional consequences of mGlu4 RNA editing. (PMID:34244459)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	grm4	ENSDARG00000040156
mus_musculus	Grm4	ENSMUSG00000063239
rattus_norvegicus	Grm4	ENSRNOG00000000487
drosophila_melanogaster	mGluR	FBGN0019985

Paralogs (7): GRM6 (ENSG00000113262), GRM1 (ENSG00000152822), GRM2 (ENSG00000164082), GRM5 (ENSG00000168959), GRM8 (ENSG00000179603), GRM7 (ENSG00000196277), GRM3 (ENSG00000198822)

Protein

Protein identifiers

Metabotropic glutamate receptor 4 — Q14833 (reviewed: Q14833)

All UniProt accessions (5): A1L4F9, B7ZLU9, Q14833, V9GYB0, V9GYR3

UniProt curated annotations — full annotation on UniProt →

Function. G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity.

Subunit / interactions. Interacts with PICK1.

Subcellular location. Cell membrane.

Tissue specificity. Strongly expressed in the cerebellum. Expressed at low levels in hippocampus, hypothalamus and thalamus. No expression detected in liver.

Similarity. Belongs to the G-protein coupled receptor 3 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q14833-1	1	yes
Q14833-2	2
Q14833-3	3
Q14833-4	4
Q14833-5	5

RefSeq proteins (6): NP_000832, NP_001243738, NP_001243740, NP_001243741, NP_001243742, NP_001269776 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000162	GPCR_3_mtglu_rcpt	Family
IPR000337	GPCR_3	Family
IPR001786	GPCR_3_mGluR4	Family
IPR001828	ANF_lig-bd_rcpt	Domain
IPR011500	GPCR_3_9-Cys_dom	Domain
IPR017978	GPCR_3_C	Domain
IPR017979	GPCR_3_CS	Conserved_site
IPR028082	Peripla_BP_I	Homologous_superfamily
IPR038550	GPCR_3_9-Cys_sf	Homologous_superfamily
IPR050726	mGluR	Family

Pfam: PF00003, PF01094, PF07562

UniProt features (106 total): helix 28, strand 24, turn 10, topological domain 8, disulfide bond 8, transmembrane region 7, splice variant 6, binding site 5, glycosylation site 5, sequence variant 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8JD4	ELECTRON MICROSCOPY	2.9
8JD6	ELECTRON MICROSCOPY	3.4
8JD5	ELECTRON MICROSCOPY	3.6
8WGB	ELECTRON MICROSCOPY	3.7
7E9H	ELECTRON MICROSCOPY	4
8WGD	ELECTRON MICROSCOPY	4.45
8WG9	ELECTRON MICROSCOPY	4.46
8WGC	ELECTRON MICROSCOPY	5.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14833-F1	83.76	0.54

Antibody-complex structures (SAbDab): 3 — 7E9H, 8JD5, 8JD6

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 (5): 159; 180–182; 230; 312; 405

Disulfide bonds (8): 67–109, 249–538, 372–388, 428–435, 520–539, 524–542, 545–557, 560–573

Glycosylation sites (5): 98, 301, 454, 484, 569

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-418594	G alpha (i) signalling events
R-HSA-420499	Class C/3 (Metabotropic glutamate/pheromone receptors)
R-HSA-9717207	Sensory perception of sweet, bitter, and umami (glutamate) taste

MSigDB gene sets: 138 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, MODULE_274, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_G_PROTEIN_COUPLED_GLUTAMATE_RECEPTOR_SIGNALING_PATHWAY, GOBP_CELL_CELL_SIGNALING, GCM_MYCL1, GCM_PRKCG, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GCM_RING1, GCM_FCGR2B, GCM_DPF2, CAR_MYST2, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION

GO Biological Process (10): adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway (GO:0007196), G protein-coupled glutamate receptor signaling pathway (GO:0007216), chemical synaptic transmission (GO:0007268), neurotransmitter secretion (GO:0007269), positive regulation of MAPK cascade (GO:0043410), regulation of neuron apoptotic process (GO:0043523), regulation of synaptic transmission, glutamatergic (GO:0051966), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193)

GO Molecular Function (3): adenylate cyclase inhibiting G protein-coupled glutamate receptor activity (GO:0001640), G protein-coupled receptor activity (GO:0004930), glutamate receptor activity (GO:0008066)

GO Cellular Component (5): plasma membrane (GO:0005886), cytoplasmic vesicle (GO:0031410), presynapse (GO:0098793), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
GPCR downstream signalling	1
GPCR ligand binding	1
Sensory perception of taste	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
G protein-coupled glutamate receptor activity	2
transmembrane signaling receptor activity	2
cellular anatomical structure	2
adenylate cyclase inhibiting G protein-coupled glutamate receptor activity	1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1
G protein-coupled glutamate receptor signaling pathway	1
glutamate receptor signaling pathway	1
anterograde trans-synaptic signaling	1
neurotransmitter transport	1
chemical synaptic transmission	1
establishment of localization in cell	1
presynapse	1
signal release from synapse	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
regulation of apoptotic process	1
neuron apoptotic process	1
synaptic transmission, glutamatergic	1
modulation of chemical synaptic transmission	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway	1
glutamate binding	1
membrane	1
cell periphery	1
cytoplasm	1
intracellular vesicle	1
synapse	1
cell junction	1

Protein interactions and networks

STRING

2027 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRM4	GRM2	Q14416	917
GRM4	GRIK1	P39086	767
GRM4	HTR1A	P08908	733
GRM4	GRIA1	P42261	722
GRM4	GRIN2A	Q12879	712
GRM4	GRM7	Q14831	663
GRM4	GRIN3A	Q8TCU5	661
GRM4	GRIA4	P48058	630
GRM4	GRIN2B	Q13224	622
GRM4	GRIN2C	Q14957	580
GRM4	HOMER1	Q86YM7	579
GRM4	GRIN2D	O15399	570
GRM4	GRIK4	Q16099	566
GRM4	GRID1	Q9ULK0	551
GRM4	GRIA3	P42263	545

IntAct

2 interactions, top by confidence:

A	B	Type	Score
GRM4	GRM7	psi-mi:“MI:0914”(association)	0.350

BioGRID (3): GRM4 (Affinity Capture-MS), CD99L2 (Affinity Capture-MS), GRM7 (Affinity Capture-MS)

ESM2 similar proteins: A2A259, A2AIR5, H2Q5A1, O00222, O15399, O60242, O75077, O75882, O97741, P15209, P24786, P31423, P35400, P37088, P47743, P55270, P70579, Q00961, Q01098, Q03351, Q03391, Q13507, Q14833, Q14957, Q16288, Q1ZZH0, Q4R766, Q5IS37, Q5RDQ8, Q62645, Q63604, Q68ED2, Q68EF4, Q6AYT7, Q80ZF8, Q8CIW5, Q8TCU5, Q8VHN2, Q91044, Q91YD4

Diamond homologs: O00222, O15303, O62714, P23385, P31421, P31422, P31423, P31424, P35349, P35400, P41180, P41594, P47743, P48442, P70579, P91685, P97772, Q09630, Q13255, Q14416, Q14831, Q14832, Q14833, Q14BI2, Q1ZZH0, Q1ZZH1, Q3UVX5, Q5NCH9, Q5RAL3, Q5RDQ8, Q68ED2, Q68EF4, Q863I4, Q9QY96, Q9QYS2, P35384, A3QNZ8, A3QNZ9, A3QP00, A3QP01

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
“glutamic acid”	“up-regulates activity”	GRM4	“chemical activation”
GRM4	“up-regulates activity”	GNAS	binding
GRM4	up-regulates	Excitatory_synaptic_transmission
GRM4	“up-regulates quantity”	calcium(2+)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	123
Likely benign	3
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

3155 predictions. Top by Δscore:

Variant	Effect	Δscore
6:34028115:CTCA:C	donor_loss	1.0000
6:34028116:TCACC:T	donor_loss	1.0000
6:34028117:CACCT:C	donor_loss	1.0000
6:34028119:C:CT	donor_loss	1.0000
6:34040174:TTA:T	donor_loss	1.0000
6:34040175:TA:T	donor_loss	1.0000
6:34040176:A:AC	donor_gain	1.0000
6:34040176:AC:A	donor_loss	1.0000
6:34040177:C:CC	donor_gain	1.0000
6:34040177:CT:C	donor_gain	1.0000
6:34040572:A:AC	donor_gain	1.0000
6:34040573:C:CC	donor_gain	1.0000
6:34040576:A:AC	donor_gain	1.0000
6:34040576:AAG:A	donor_gain	1.0000
6:34040577:A:C	donor_gain	1.0000
6:34056542:A:AC	donor_gain	1.0000
6:34056543:C:CA	donor_gain	1.0000
6:34056544:TGGTG:T	donor_gain	1.0000
6:34056553:T:TA	donor_gain	1.0000
6:34056553:TCTTG:T	donor_gain	1.0000
6:34056683:GCCTG:G	acceptor_loss	1.0000
6:34056685:C:CC	acceptor_gain	1.0000
6:34056686:T:G	acceptor_loss	1.0000
6:34061888:CTCA:C	donor_loss	1.0000
6:34061889:TCA:T	donor_loss	1.0000
6:34061890:CA:C	donor_loss	1.0000
6:34061891:A:AC	donor_gain	1.0000
6:34061891:A:AG	donor_loss	1.0000
6:34061892:C:CC	donor_gain	1.0000
6:34061902:T:TA	donor_gain	1.0000

AlphaMissense

5958 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:34035718:A:G	W798R	1.000
6:34035718:A:T	W798R	1.000
6:34035767:G:C	F781L	1.000
6:34035767:G:T	F781L	1.000
6:34035769:A:G	F781L	1.000
6:34036074:C:G	R679P	1.000
6:34036083:C:G	R676P	1.000
6:34036257:A:T	V618D	1.000
6:34036490:C:A	W540C	1.000
6:34036490:C:G	W540C	1.000
6:34040658:A:G	L420P	1.000
6:34040683:C:G	A412P	1.000
6:34056548:G:C	C388W	1.000
6:34056549:C:G	C388S	1.000
6:34056550:A:G	C388R	1.000
6:34056550:A:T	C388S	1.000
6:34056596:G:C	C372W	1.000
6:34056597:C:A	C372F	1.000
6:34056597:C:G	C372S	1.000
6:34056597:C:T	C372Y	1.000
6:34056598:A:G	C372R	1.000
6:34056598:A:T	C372S	1.000
6:34056614:C:A	W366C	1.000
6:34056614:C:G	W366C	1.000
6:34056616:A:G	W366R	1.000
6:34056616:A:T	W366R	1.000
6:34056627:A:C	F362C	1.000
6:34056627:A:G	F362S	1.000
6:34056629:C:A	W361C	1.000
6:34056629:C:G	W361C	1.000

dbSNP variants (sampled 300 via entrez): RS1000004732 (6:34140387 C>T), RS1000009201 (6:34123144 C>A), RS1000016850 (6:34033153 C>T), RS1000047345 (6:34136657 A>G), RS1000061662 (6:34122930 A>G), RS1000067510 (6:34079204 CGCCTCACGTCACCTGCT>C), RS1000075271 (6:34148731 C>A,G), RS1000089730 (6:34130916 C>A), RS1000100880 (6:34072042 A>C), RS1000112734 (6:34124888 A>G,T), RS1000134435 (6:34155392 C>G,T), RS1000170149 (6:34134015 G>C), RS1000186514 (6:34090453 G>A), RS1000187198 (6:34155055 C>G,T), RS1000190805 (6:34050258 G>A)

Disease associations

OMIM: gene MIM:604100 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST002056_1	Osteosarcoma	8.000000e-09
GCST002740_10	Inflammatory skin disease	3.000000e-06
GCST003831_46	Asthma	5.000000e-09
GCST003832_25	Asthma (childhood onset)	7.000000e-06
GCST003995_33	Tonsillectomy	4.000000e-08
GCST004904_32	Body mass index	1.000000e-13
GCST004904_68	Body mass index	3.000000e-14
GCST005014_125	Tonsillectomy	4.000000e-08
GCST005951_153	Body mass index	5.000000e-09
GCST006920_1	Regular attendance at a gym or sports club	4.000000e-08
GCST007269_266	Pulse pressure	8.000000e-09
GCST007485_6	Anthropometric traits	7.000000e-109
GCST007490_13	Anthropometric traits (multi-trait analysis)	3.000000e-69
GCST009158_11	Uterine fibroids	3.000000e-08
GCST009282_1	BMI at birth	4.000000e-07
GCST011927_1	HDL levels x fish oil supplementation interaction (2df)	1.000000e-19
GCST011971_9	Weight	5.000000e-14
GCST011972_2	Height	2.000000e-21
GCST011972_39	Height	2.000000e-21
GCST011972_49	Height	6.000000e-21
GCST012227_936	Hip circumference adjusted for BMI	2.000000e-08
GCST012228_261	Waist-hip index	2.000000e-12
GCST012230_451	Waist-to-hip ratio adjusted for BMI	4.000000e-11
GCST90000025_489	Appendicular lean mass	3.000000e-10
GCST90002393_22	Monocyte count	9.000000e-11
GCST90002409_35	Childhood body mass index	2.000000e-06
GCST90020024_1113	A body shape index	6.000000e-41
GCST90020025_709	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST90020025_710	Waist-to-hip ratio adjusted for BMI	2.000000e-40
GCST90020027_1078	Waist-hip index	3.000000e-09

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0007924	tonsillectomy risk measurement
EFO:0004340	body mass index
EFO:0009592	social interaction measurement
EFO:0005763	pulse pressure measurement
EFO:0004324	body weights and measures
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0600007	fish oil supplement exposure measurement
EFO:0004338	body weight
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004980	appendicular lean mass
EFO:0005091	monocyte count
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2736 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 980,812 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL575060	GLUTAMIC ACID	3	929,756
CHEMBL284377	DEXFOSFOSERINE	2	50,984
CHEMBL4089083	FOLIGLURAX	2	72

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Metabotropic glutamate receptors

Most potent curated ligand interactions (34 total), top 25:

Ligand	Action	Affinity	Parameter
compound 22a [PMID: 21688779]	Positive	8.1	pEC50
FP0429	Full agonist	7.4	pEC50
ADX88178	Positive	7.4	pKi
VU2957	Positive	7.19	pEC50
foliglurax	Positive	7.12	pEC50
LSP4-2022	Agonist	6.96	pEC50
SIB-1893	Positive	6.8	pEC50
compound 1 [PMID: 22465637]	Positive	6.7	pEC50
VU0361737	Positive	6.6	pEC50
MPEP	Positive	6.6	pEC50
L-AP4	Agonist	6.5	pEC50
VU0400195	Positive	6.5	pEC50
VU0359516	Positive	6.4	pEC50
[3H]AP4	Full agonist	6.3	pKd
Lu AF21934	Positive	6.3	pEC50
VU0001171	Positive	6.2	pEC50
VU0155041	Positive	6.1	pEC50
compound 7 [PMID: 20638279]	Positive	6.0	pEC50
VU0364770	Positive	6.0	pEC50
compound 11 [PMID: 20638279]	Positive	6.0	pEC50
L-serine-O-phosphate	Agonist	5.9	pEC50
VU0092145	Positive	5.7	pEC50
LSP1-2111	Agonist	5.66	pEC50
L-glutamic acid	Agonist	5.5	pEC50
(R,S)-4-PPG	Full agonist	5.3	pEC50

Binding affinities (BindingDB)

613 measured of 632 human assays (670 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(furan-3-yl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester	EC50	0.3 nM
5-(difluoromethyl)-N-[(1S)-1-(1-ethyl-5-fluorobenzimidazol-2-yl)-2-methylpropyl]pyrazine-2-carboxamide	IC50	4 nM	US-12421218: Substituted pyrazine-carboxamide derivatives
1-(difluoromethyl)-N- (1H-pyrazolo [4,3-b]pyridin-3- yl)isoquinolin-6-amine	EC50	8 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-(1-fluoro-1-methyl- ethyl)-N-(1H- pyrazolo[3,4-b]pyrazin- 3-yl)isoquinolin-6-amine	EC50	8 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
4-fluoro-1-methyl-N- (1H-pyrazolo[4,3-b] pyridin-3- yl)isoquinolin-6-amine	EC50	13 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-(difluoromethyl)-N- (1H-pyrazolo[3,4-b] pyrazin-3- yl)isoquinolin-6-amine	EC50	13 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-(1,1-difluoroethyl)-N- (1H- pyrazolo[3,4-b]pyridin-3- yl)isoquinolin-6-amine	EC50	13.8 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-chloro-4-fluoro-N- (1H-pyrazolo[4,3-b] pyridin-3- yl)isoquinolin-6-amine	EC50	15 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,7-dimethyl-4aH-thieno[3,2-d]pyrimidin-1-ium-2,4-dione	EC50	16 nM	US-9676732: Ethynyl derivatives
6-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-4-methyl-1,3,3a,7a-tetrahydro-[1,2,5]thiadiazolo[3,4-d]pyrimidine-5,7-dione	EC50	17 nM	US-9676732: Ethynyl derivatives
N-(1H-pyrazolo[4,3-b] pyridin-3-yl)-1- (trifluoromethyl) isoquinolin-6-amine	EC50	18 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-(1,1-difluoroethyl)-N- (1H- pyrazolo[4,3-b]pyridin-3- yl)isoquinolin-6-amine	EC50	20.1 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-ethyl-4-fluoro-N-(1H- pyrazolo[4,3-b]pyridin-3 yl)isoquinolin-6-amine	EC50	22 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
6-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-4-propan-2-yl-1,3,3a,7a-tetrahydro-[1,2,5]thiadiazolo[3,4-d]pyrimidine-5,7-dione	EC50	23 nM	US-9676732: Ethynyl derivatives
1-(1-fluoro-1-methyl- ethyl)- N-(1H-pyrazolo[4,3-b] pyridin- 3-yl)isoquinolin-6-amine	EC50	23.1 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
3-propyl-N-(1H- pyrazolo[3,4-b] pyrazine-3- yl)benzo[d]isothiazol- 6-amine	EC50	23.4 nM	US-10221172: Benzothiazole and benzisothiazole-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1-methyl-8-methylidenequinazolin-1-ium-2,4-dione	EC50	26 nM	US-9676732: Ethynyl derivatives
5-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,7-dimethyl-3aH-pyrazolo[3,4-d]pyrimidin-1-ium-4,6-dione	EC50	26 nM	US-9676732: Ethynyl derivatives
4-fluoro-1-(2-furyl)-N- (1H-pyrazolo[4,3-b] pyridin-3- yl)isoquinolin-6-amine	EC50	28 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-cyclopropyl-4-fluoro- N-(1H-pyrazolo[4,3-b] pyridin-3- yl)isoquinolin-6-amine	EC50	28 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-(1,1-difluoroburyl)-N- (1H- pyrazolo[3,4-b]pyrazin-3- yl)isoquinolin-6-amine	EC50	28.6 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
3-[2,6-difluoro-4-(2-pyridin-3-ylethynyl)phenyl]-1,7-dimethyl-4aH-thieno[3,2-d]pyrimidin-1-ium-2,4-dione	EC50	29 nM	US-9676732: Ethynyl derivatives
(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione	EC50	29 nM	US-10011607: Ethynyl derivatives
6-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-methyl-4-propan-2-yl-1,7a-dihydropyrazolo[4,3-d]pyrimidine-5,7-dione	EC50	30 nM	US-9676732: Ethynyl derivatives
N-[1-methyl-3-(oxolan-3-ylmethoxy)indazol-6-yl]-1H-pyrazolo[4,3-b]pyridin-3-amine	EC50	30.5 nM	US-10508105
N-(1H-pyrazolo[3,4- b]pyrazin-3-yl)-1- (trifluoromethyl) isoquinolin-6-amine	EC50	31 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
(9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione	EC50	31 nM	US-10011607: Ethynyl derivatives
1-(1,1-difluoro-2-methyl- propyl)-N-(1H-pyrazolo [4,3-b]pyridin-3-yl) isoquinolin-6-amine	EC50	31.4 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
3-[2-chloro-4-(2-phenylethynyl)phenyl]-8-methoxy-1-methyl-8H-quinazolin-1-ium-2,4-dione	EC50	32 nM	US-9676732: Ethynyl derivatives
N-(3-chloro-5-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine	EC50	32 nM	US-9163015: Pyrazolopyridine, pyrarolopyrazine, pyrazolopyrimidine, pyrazolothiophene and pyrazolothiazole compounds as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
6-((1H-pyrazolo[4,3-b] pyridin- 3-yl)amino)-N-(3,3- difluorocyclobutyl)benzo[d] isothiazole-3-carboxamide	EC50	32 nM	US-10221172: Benzothiazole and benzisothiazole-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
6-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-4-methyl-7aH-[1,3]thiazolo[4,5-d]pyrimidin-4-ium-5,7-dione	EC50	33 nM	US-9676732: Ethynyl derivatives
N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine	EC50	33 nM	US-9163015: Pyrazolopyridine, pyrarolopyrazine, pyrazolopyrimidine, pyrazolothiophene and pyrazolothiazole compounds as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-ethoxy-N-(1H-pyrazolo [4,3-b]pyridin-3-yl) isoquinolin-6-amine	EC50	33 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-(1,1-difluorobutyl)-N- (1H- pyrazolo[4,3-b]pyridin-3- yl)isoquinolin-6-amine	EC50	34.4 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione	EC50	36 nM	US-10011607: Ethynyl derivatives
6-[2-chloro-6-fluoro-4-(2-pyridin-3-ylethynyl)phenyl]-2-methyl-4-propan-2-yl-1,7a-dihydropyrazolo[4,3-d]pyrimidine-5,7-dione	EC50	37 nM	US-9676732: Ethynyl derivatives
3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-8-methoxy-1-methyl-8H-quinazolin-1-ium-2,4-dione	EC50	38 nM	US-9676732: Ethynyl derivatives
3-ethyl-N-(1H- pyrazolo[4,3-b] pyridin-3- yl)isothiazolo [4,5-b]pyridin-6- amine	EC50	38.3 nM	US-10221172: Benzothiazole and benzisothiazole-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
N-(6-fluoro-1H-pyrazolo [4,3-b]pyridin-3-yl)-1- (trifluoromethyl) isoquinolin-6-amine	EC50	38.5 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-(1-fluoro-1-methyl- ethyl)- N-(1H-pyrazolo[3,4-b] pyridin- 3-yl)isoquinolin-6-amine	EC50	38.8 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione	EC50	39 nM	US-10011607: Ethynyl derivatives
1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(2H-pyrazolo[3,4-b]pyrazin-3-yl)isoquinolin-6-amine	EC50	39.1 nM	US-11242342: Isoquinoline amine compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
N-(1H-pyrazolo[4,3-b] pyridin-3-yl)-1-(1,1,1- trifluoropropan-2- yl)isoquinolin-6-amine	EC50	42 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
6-((1H-pyrazolo[3,4-b] pyrazin-3- yl)amino)-N-(3,3- difluorocyclobutyl) benzo[d] isothiazole-3- carboxamide	EC50	42.6 nM	US-10221172: Benzothiazole and benzisothiazole-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
N-(3,5-dichlorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine	EC50	43 nM	US-9163015: Pyrazolopyridine, pyrarolopyrazine, pyrazolopyrimidine, pyrazolothiophene and pyrazolothiazole compounds as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-(difluoromethyl)-N- (1H-pyrazolo [3,4-b]pyrazin-3- yl)isoquinolin-6-amine	EC50	43 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
1-(fluoromethyl)-N-(1H- pyrazolo[4,3-b]pyridin- 3-yl)isoquinolin-6- amine	EC50	44 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
N-[5-[(4-chloro-2-fluorophenyl)methylsulfonyl]-1,3-thiazol-2-yl]pyridine-2-carboxamide	EC50	44.1 nM	US-9192603: Heterocyclic sulfone mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
N-(3,3- difluorocycloburyl)- 6-(1H-pyrazolo[4,3-b] pyridin-3- ylamino)naphthalene- 1-carboxamide	EC50	45 nM	US-10227343: Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction

ChEMBL bioactivities

1710 potent at pChembl≥5 of 1766 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.19	EC50	0.065	nM	CHEMBL3798517
10.02	EC50	0.095	nM	CHEMBL3798234
9.63	EC50	0.236	nM	CHEMBL3798197
9.50	EC50	0.319	nM	CHEMBL3797445
9.16	EC50	0.689	nM	CHEMBL3799261
9.12	EC50	0.758	nM	CHEMBL3797923
9.04	EC50	0.921	nM	CHEMBL3797463
8.90	EC50	1.25	nM	CHEMBL3797390
8.89	EC50	1.28	nM	CHEMBL3798366
8.87	EC50	1.35	nM	CHEMBL3798239
8.79	EC50	1.61	nM	CHEMBL3799708
8.73	EC50	1.86	nM	CHEMBL3797777
8.66	EC50	2.19	nM	CHEMBL3798945
8.60	EC50	2.52	nM	CHEMBL3799281
8.55	EC50	2.8	nM	CHEMBL3799999
8.49	IC50	3.2	nM	CHEMBL3609741
8.49	IC50	3.2	nM	CHEMBL3609742
8.49	IC50	3.236	nM	CHEMBL3609741
8.49	IC50	3.236	nM	CHEMBL3609742
8.43	IC50	3.7	nM	CHEMBL3609743
8.43	IC50	3.715	nM	CHEMBL3609743
8.40	EC50	4	nM	CHEMBL3609729
8.40	EC50	3.96	nM	CHEMBL3798583
8.40	EC50	4	nM	CHEMBL4097743
8.40	EC50	4	nM	CHEMBL4070594
8.34	IC50	4.6	nM	CHEMBL541754
8.34	IC50	4.571	nM	CHEMBL541754
8.31	IC50	4.9	nM	CHEMBL1300476
8.31	IC50	4.898	nM	CHEMBL1300476
8.29	IC50	5.1	nM	CHEMBL562551
8.29	IC50	5.129	nM	CHEMBL562551
8.28	IC50	5.3	nM	CHEMBL3609738
8.28	IC50	5.248	nM	CHEMBL3609738
8.22	EC50	6	nM	CHEMBL4105462
8.18	IC50	6.607	nM	CHEMBL3609734
8.17	IC50	6.7	nM	CHEMBL3609734
8.15	EC50	7	nM	CHEMBL1830711
8.14	IC50	7.3	nM	CHEMBL3608323
8.13	IC50	7.4	nM	CHEMBL3609737
8.13	IC50	7.413	nM	CHEMBL3608323
8.13	IC50	7.413	nM	CHEMBL3609737
8.10	EC50	8	nM	CHEMBL4779331
8.10	EC50	8	nM	CHEMBL5768117
8.05	EC50	9	nM	CHEMBL1830711
8.05	EC50	9	nM	CHEMBL1830707
8.00	EC50	10	nM	CHEMBL4082573
7.98	IC50	10.4	nM	CHEMBL3609736
7.98	IC50	10.47	nM	CHEMBL3609736
7.98	EC50	10.4	nM	CHEMBL5991620
7.96	IC50	11	nM	CHEMBL3357575

PubChem BioAssay actives

777 with measured affinity, of 2052 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-amino-N-[3-chloro-4-(1,3-dioxoisoindol-2-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0001	uM
3-amino-N-[3-chloro-4-(5-ethylpyrimidin-2-yl)oxyphenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0001	uM
3-amino-N-[3-chloro-4-(3-oxo-1H-isoindol-2-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0002	uM
3-amino-N-[3-chloro-4-(5-methoxy-3-oxo-1H-isoindol-2-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0003	uM
3-amino-N-[3-chloro-4-(4-methyl-1,3-dioxoisoindol-2-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0007	uM
3-amino-N-[4-(4-benzyl-2-oxopyrrolidin-1-yl)-3-chlorophenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0008	uM
3-amino-N-[3-chloro-4-(1-oxo-3,4-dihydroisoquinolin-2-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0009	uM
3-amino-N-[3-chloro-4-(5-oxo-7H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0013	uM
3-amino-N-[3-chloro-4-(3-oxo-2-azaspiro[4.5]decan-2-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0013	uM
3-amino-N-[3-chloro-4-(2-methylpyrimidin-5-yl)oxyphenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0014	uM
3-amino-N-[3-chloro-4-[4-(2-methylpropyl)-2-oxopyrrolidin-1-yl]phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0016	uM
3-amino-N-[3-chloro-4-[4-(2-chloro-6-fluorophenyl)-2-oxopyrrolidin-1-yl]phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0019	uM
3-amino-N-[3-chloro-4-(3-oxo-1,4-dihydroisoquinolin-2-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0022	uM
3-amino-N-[3-chloro-4-(2-oxo-4-pyridin-3-ylpyrrolidin-1-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0025	uM
3-amino-N-[3-chloro-4-(4-cyclopropyl-4-methyl-2-oxopyrrolidin-1-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0028	uM
N-[4-chloro-3-(fluoromethoxy)phenyl]pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0032	uM
N-[4-chloro-3-[dideuterio(fluoro)methoxy]phenyl]pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0032	uM
N-[3-[dideuterio(fluoro)methoxy]phenyl]pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0037	uM
3-amino-N-[3-chloro-4-(1-methyl-3-oxo-1H-isoindol-2-yl)phenyl]pyridine-2-carboxamide	1298678: Positive allosteric modulator activity at human mGlu4 receptor expressed in CHO cells expressing Gqi5 by calcium mobilization assay	ec50	0.0040	uM
(NE)-N-[6-[[1-(2-methyl-3-pyridinyl)piperidin-4-yl]methyl]-2-thieno[3,2-c]pyridin-6-ylchromen-4-ylidene]hydroxylamine	1451892: Positive allosteric modulation of recombinant human mGlu4 receptor expressed in HEK293 cells co-expressing Gi/Gq assessed as increase in glutamate-induced calcium flux preincubated for 10 mins followed by glutamate addition measured for 3 mins by Fluo4-AM dye based fluorescence assay	ec50	0.0040	uM
(NE)-N-[6-(1-pyridin-3-ylazetidin-3-yl)oxy-2-thieno[3,2-c]pyridin-6-ylchromen-4-ylidene]hydroxylamine	1451892: Positive allosteric modulation of recombinant human mGlu4 receptor expressed in HEK293 cells co-expressing Gi/Gq assessed as increase in glutamate-induced calcium flux preincubated for 10 mins followed by glutamate addition measured for 3 mins by Fluo4-AM dye based fluorescence assay	ec50	0.0040	uM
5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-1,3-thiazol-2-amine	1242925: Positive allosteric modulator activity at human mGlu4 receptor	ec50	0.0040	uM
N-[3-(difluoromethoxy)phenyl]pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0046	uM
N-(3-methylsulfanylphenyl)pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0049	uM
N-(4-chloro-3-methoxyphenyl)pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0051	uM
N-(4-chloro-3-cyanophenyl)pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0052	uM
1-[4-[[(4E)-4-hydroxyimino-2-thieno[3,2-c]pyridin-6-ylchromen-6-yl]oxymethyl]piperidin-1-yl]ethanone	1451892: Positive allosteric modulation of recombinant human mGlu4 receptor expressed in HEK293 cells co-expressing Gi/Gq assessed as increase in glutamate-induced calcium flux preincubated for 10 mins followed by glutamate addition measured for 3 mins by Fluo4-AM dye based fluorescence assay	ec50	0.0060	uM
N-[3-(difluoromethoxy)phenyl]-6-fluoropyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0066	uM
N-pyrimidin-2-yl-5-thia-3,11,12-triazatricyclo[8.3.0.02,6]trideca-1(10),2(6),3,12-tetraen-4-amine	618715: Positive allosteric modulation of human mGlu4 receptor expressed in BHK cells assessed as potentiation of glutamate-induced calcium mobilization after 1 hr by FLIPR assay	ec50	0.0070	uM
N-(4-chloro-3-methoxyphenyl)-6-fluoropyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0073	uM
N-(3-cyano-4-fluorophenyl)pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0074	uM
1-(difluoromethyl)-N-(1H-pyrazolo[4,3-b]pyridin-3-yl)isoquinolin-6-amine	1671504: Positive allosteric modulator activity at human mGlu4 receptor/Gqi5 in presence of EC20 glutamate by calcium mobilization assay	ec50	0.0080	uM
N-pyridin-2-yl-5-thia-3,11,12-triazatricyclo[8.3.0.02,6]trideca-1(10),2(6),3,12-tetraen-4-amine	618715: Positive allosteric modulation of human mGlu4 receptor expressed in BHK cells assessed as potentiation of glutamate-induced calcium mobilization after 1 hr by FLIPR assay	ec50	0.0090	uM
1-[4-[(4E)-4-hydroxyimino-2-pyrrolo[1,2-c]pyrimidin-3-ylchromen-6-yl]oxypiperidin-1-yl]ethanone	1451892: Positive allosteric modulation of recombinant human mGlu4 receptor expressed in HEK293 cells co-expressing Gi/Gq assessed as increase in glutamate-induced calcium flux preincubated for 10 mins followed by glutamate addition measured for 3 mins by Fluo4-AM dye based fluorescence assay	ec50	0.0100	uM
N-(3-cyanophenyl)pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0104	uM
N-[3-chloro-4-(4-methyl-1,3-dioxoisoindol-2-yl)phenyl]pyridine-2-carboxamide	1169626: Displacement of [3H]-N-(4-{[(2- Chlorophenyl)amino]sulfonyl} phenyl )pyridine-2-carboxamide from human mGlu4 receptor after 30 mins by scintillation counting analysis	ic50	0.0110	uM
N-[3-bromo-4-(4-methyl-1,3-dioxoisoindol-2-yl)phenyl]pyridine-2-carboxamide	1169626: Displacement of [3H]-N-(4-{[(2- Chlorophenyl)amino]sulfonyl} phenyl )pyridine-2-carboxamide from human mGlu4 receptor after 30 mins by scintillation counting analysis	ic50	0.0120	uM
5-methyl-4-(1H-pyrazol-4-yl)-N-pyridin-2-yl-1,3-thiazol-2-amine	618715: Positive allosteric modulation of human mGlu4 receptor expressed in BHK cells assessed as potentiation of glutamate-induced calcium mobilization after 1 hr by FLIPR assay	ec50	0.0130	uM
N-(3-methoxyphenyl)pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0137	uM
(NE)-N-[6-[(3R)-1-pyrimidin-4-ylpyrrolidin-3-yl]oxy-2-thieno[3,2-c]pyridin-6-ylchromen-4-ylidene]hydroxylamine	1451892: Positive allosteric modulation of recombinant human mGlu4 receptor expressed in HEK293 cells co-expressing Gi/Gq assessed as increase in glutamate-induced calcium flux preincubated for 10 mins followed by glutamate addition measured for 3 mins by Fluo4-AM dye based fluorescence assay	ec50	0.0170	uM
N-(1H-pyrazolo[4,3-b]pyridin-3-yl)-1-(trifluoromethyl)isoquinolin-6-amine	1671504: Positive allosteric modulator activity at human mGlu4 receptor/Gqi5 in presence of EC20 glutamate by calcium mobilization assay	ec50	0.0180	uM
(NE)-N-[6-[3-(2-methyl-4-pyridinyl)propoxy]-2-pyrrolo[1,2-c]pyrimidin-3-ylchromen-4-ylidene]hydroxylamine	1451892: Positive allosteric modulation of recombinant human mGlu4 receptor expressed in HEK293 cells co-expressing Gi/Gq assessed as increase in glutamate-induced calcium flux preincubated for 10 mins followed by glutamate addition measured for 3 mins by Fluo4-AM dye based fluorescence assay	ec50	0.0190	uM
N-(3-cyclopropyl-1-methylindazol-6-yl)-2H-pyrazolo[3,4-b]pyrazin-3-amine	1397000: Positive allosteric modulation of human mGluR4 expressed in CHO cells co-expressing Gqi5 assessed as increase in glutamate-induced calcium flux preincubated for 2.5 mins followed by glutamate addition by Fluo-4-AM dye based fluorescence assay	ec50	0.0198	uM
N-[3-chloro-4-[(2-chlorophenyl)sulfamoyl]phenyl]pyridine-2-carboxamide	1304378: Positive allosteric modulation of human mGlu4 receptor	ec50	0.0198	uM
7-fluoro-3-methyl-N-(2H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2-benzoxazol-5-amine	1513746: Positive allosteric modulation of human mGlu4 receptor expressed in CHO cells co-expressing Gqi5 assessed as increase in glutamate-induced calcium mobilization preincubated for 142 secs followed by EC20 glutamate addition and subsequent EC80 glutamate addition after 147 secs by Fluo-4-AM dye based fluorescence assay	ec50	0.0229	uM
N-[1-methyl-3-(1-methylcyclopropyl)indazol-6-yl]-2H-pyrazolo[3,4-b]pyrazin-3-amine	1397000: Positive allosteric modulation of human mGluR4 expressed in CHO cells co-expressing Gqi5 assessed as increase in glutamate-induced calcium flux preincubated for 2.5 mins followed by glutamate addition by Fluo-4-AM dye based fluorescence assay	ec50	0.0249	uM
(NE)-N-[6-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-2-thieno[3,2-c]pyridin-6-ylchromen-4-ylidene]hydroxylamine	1451892: Positive allosteric modulation of recombinant human mGlu4 receptor expressed in HEK293 cells co-expressing Gi/Gq assessed as increase in glutamate-induced calcium flux preincubated for 10 mins followed by glutamate addition measured for 3 mins by Fluo4-AM dye based fluorescence assay	ec50	0.0250	uM
N-(3,3-difluorocyclobutyl)-6-(2H-pyrazolo[3,4-b]pyrazin-3-ylamino)-1,2-benzothiazole-3-carboxamide	1513746: Positive allosteric modulation of human mGlu4 receptor expressed in CHO cells co-expressing Gqi5 assessed as increase in glutamate-induced calcium mobilization preincubated for 142 secs followed by EC20 glutamate addition and subsequent EC80 glutamate addition after 147 secs by Fluo-4-AM dye based fluorescence assay	ec50	0.0260	uM
N-[4-[(2-chlorophenyl)sulfamoyl]phenyl]pyridine-2-carboxamide	501614: Positive allosteric modulation of human mGlu4 receptor expressed in CHO cells assessed as potentiation of glutamate-induced calcium mobilization	ec50	0.0270	uM
N-(4-fluoro-3-methoxyphenyl)pyridine-2-carboxamide	1242927: Displacement of [3H]N-(4-chloro-3-methoxyphenyl)picolinamide from human mGlu4 receptor expressed in CHO cell membranes incubated for 30 mins by liquid scintillation counting method	ic50	0.0316	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
propionaldehyde	increases expression	1
bisphenol A	affects methylation	1
afimoxifene	increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	increases abundance, affects methylation	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
tertiapin	increases activity, increases import, affects binding, decreases reaction	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
pentanal	increases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
fenpyroximate	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
pyrimidifen	decreases expression	1
thifluzamide	decreases expression	1
pyrachlostrobin	decreases expression	1
4-styrylpyrimidin-2-ylamine	affects binding	1
picoxystrobin	decreases expression	1
Aldehydes	increases expression	1
Antimycin A	decreases expression	1
Atrazine	increases expression	1
Atropine	affects binding, decreases reaction, increases activity, increases import	1
Cannabinoids	affects methylation, increases abundance	1
Carbachol	affects binding, decreases reaction, increases activity, increases import	1

ChEMBL screening assays

252 unique, capped per target: 161 functional, 91 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1013093	Functional	Activity at mGluR4 assessed as calcium mobilization by FLIPR	Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotropic glutamate receptor subtypes 5, 6, and 7. — J Med Chem
CHEMBL1018994	Binding	Displacement of [3H]Quisqualate from human mGluR4 receptor expressed in BHK cells	Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-based omega-acidic amino acids as glutamate receptors ligands. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0SU	ACTOne GRM4	Transformed cell line	Female
CVCL_KS49	MultiScreen HEK293T mGluR4	Transformed cell line	Female
CVCL_KV34	cAMP Hunter CHO-K1 GRM4 Gi	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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