GRM2

Summary

GRM2 (glutamate metabotropic receptor 2, HGNC:4594) is a protein-coding gene on chromosome 3p21.2, encoding Metabotropic glutamate receptor 2 (Q14416). Dimeric G protein-coupled receptor which is activated by the excitatory neurotransmitter L-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 2912 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 123 total
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000839

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4594
Approved symbol	GRM2
Name	glutamate metabotropic receptor 2
Location	3p21.2
Locus type	gene with protein product
Status	Approved
Aliases	GPRC1B, mGlu2, MGLUR2
Ensembl gene	ENSG00000164082
Ensembl biotype	protein_coding
OMIM	604099
Entrez	2912

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000296479, ENST00000395052, ENST00000419928, ENST00000442933, ENST00000464585, ENST00000475478, ENST00000477330, ENST00000496661, ENST00000889628, ENST00000889629, ENST00000941332

RefSeq mRNA: 3 — MANE Select: NM_000839 NM_000839, NM_001349116, NM_001349117

CCDS: CCDS2834

Canonical transcript exons

ENST00000395052 — 6 exons

Exon	Start	End
ENSE00001081269	51708848	51709433
ENSE00001816227	51707068	51707167
ENSE00001885366	51718039	51718613
ENSE00003490166	51717637	51717817
ENSE00003524897	51715062	51716137
ENSE00003694422	51712473	51713310

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 89.77.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4956 / max 109.5471, expressed in 279 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36777	1.4956	279

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	89.77	gold quality
vena cava	UBERON:0004087	84.51	silver quality
right frontal lobe	UBERON:0002810	83.79	gold quality
prefrontal cortex	UBERON:0000451	81.54	gold quality
right testis	UBERON:0004534	81.32	gold quality
left testis	UBERON:0004533	80.99	gold quality
frontal cortex	UBERON:0001870	80.75	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.63	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	80.30	gold quality
neocortex	UBERON:0001950	80.10	gold quality
endothelial cell	CL:0000115	79.79	gold quality
ganglionic eminence	UBERON:0004023	79.21	gold quality
pons	UBERON:0000988	78.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.73	gold quality
cingulate cortex	UBERON:0003027	78.55	gold quality
testis	UBERON:0000473	78.48	gold quality
anterior cingulate cortex	UBERON:0009835	78.33	gold quality
cerebral cortex	UBERON:0000956	78.16	gold quality
parotid gland	UBERON:0001831	77.50	gold quality
superior frontal gyrus	UBERON:0002661	76.83	gold quality
primary visual cortex	UBERON:0002436	76.76	gold quality
occipital lobe	UBERON:0002021	76.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.51	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	76.49	gold quality
buccal mucosa cell	CL:0002336	76.35	gold quality
Brodmann (1909) area 23	UBERON:0013554	76.19	gold quality
ventral tegmental area	UBERON:0002691	75.55	silver quality
saphenous vein	UBERON:0007318	75.23	gold quality
lateral globus pallidus	UBERON:0002476	74.88	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	74.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HDAC2

miRNA regulators (miRDB)

51 targeting GRM2, 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-12118	100.00	65.88	1270
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-606	98.72	67.34	960
HSA-MIR-6887-5P	98.56	68.49	1295

Literature-anchored findings (GeneRIF, showing 40)

• Ser-148 and Arg-183 may be important for the 3D structure and/or are involved in closure of the domain. Asp-146 is involved in differential binding properties of mGlur2. (PMID:11641422)
• Mapped to Chromosome 3p21.1 - p21.2 and has 5 exons ranging from 74 - 1076 bp. (PMID:11840499)
• The presynaptic group 2 metabotropic glutamate receptor reduces stimulated and spontaneous transmitter release in the dentate gyrus. (PMID:11897108)
• Reduction of mGluR2 immunopositive product in the stratum lacunosum moleculare of hippocampal CA1 is a consequence of neuronal loss in either the entorhinal cortex or CA1 area of the hippocampus. (PMID:15246118)
• Stimulation of glial mGluR2 through mediators present in the cerebrospinal fluid may contribute to glial proliferation and astrogliosis in amyotrophic lateral sclerosis. (PMID:15330338)
• Authors have identified and synthesized a brain penetrant propanoic acid as an allosteric potentiator of the metabotropic glutamate receptor 2. (PMID:15837331)
• The objective of this study was to assess the effects of the mGlu2/3 receptor agonist LY404039 (LY) on operant EtOH self-administration during alcohol seeking pavlovian spontaneous recovery, alcohol relapse, and maintenance responding for alcohol. (PMID:16678921)
• In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis (PMID:18297054)
• The expression of mGluR2, 3 in DA cells provide a mechanism for glutamate to modulate dopamine release in the human brain and this species-specific difference may be critical to understanding rodent models in schizophrenia. (PMID:18853337)
• findings show that the activation of mGluR2 leads to the activation of extracellular signal-related kinase pathways (PMID:19026996)
• No association is detected between GRM2 and major depressive disorder or bipolar disorder in an allele/genotype-wise or haplotype-wise analysis of Japanese patients. (PMID:19386277)
• The glutamate receptor metabotropic 2 mutants with increased structural flexibility at this position, which is crucial for pocket closure, were clearly preferred. (PMID:19402024)
• Our findings suggest that disruption of glutamate receptors like NMDAR1 and mGluR2 at the Shank-postsynaptic platform could contribute to destruction of the postsynaptic density which underlies the synaptic dysfunction and loss in Alzheimer’s disease. (PMID:19635471)
• This study demonistrated that the level of metabotropic glutamate receptor 2/3 is elevated in the prefrontal cortex in patient of major depression disorder. (PMID:19945495)
• Our results suggested that GRM2 may play a role in the pathophysiology of methamphetamine-induced psychosis but not schizophrenia in the Japanese population (PMID:20211215)
• Suggest a genetic association exists between SNPs in several genes, such as HTR2A and NRG1, and response to mGlu2/3 agonist LY2140023 treatment in schizophrenia. (PMID:21173788)
• data support the idea that glutamate release in the vental tegmental area(VTA) is critically involved in cocaine-induced reinstatement; loss of mGluR2/3-mediated regulation of glutamate release in the VTA may critically contribute to the risk of relapse (PMID:21881873)
• the structural properties for the H8 domain of the mGluR2 receptor; H8 behaves as a sensor of cholesterol concentration. (PMID:22870276)
• Only full-length dimeric mGlu2 activates G protein upon glutamate binding. (PMID:22988116)
• Three residues located at the intracellular end of transmembrane domain four are necessary for the mGlu2 receptor binding to 5TR2A. (PMID:23129762)
• the promoter methylation of the GMR2 and GMR5 genes greatly decreased the risk of schizophrenia, and the expression level of the GRM2, GRM5, and GRIA3 genes increased significantly in patients in comparison to healthy controls. (PMID:23149219)
• Human anterior cingulate cortex from alcoholic patients shows a significant reduction in mGluR(2) transcripts compared to control subjects (PMID:23407939)
• Findings suggest that mGluR2/3 and mGluR5s are unaltered in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia (PMID:24949866)
• Results demonstrate no changes in expression and density of both 5-HT2AR and mGlu2/3R in the postmortem prefrontal cortex of subjects with major depressive disorder under basal conditions; antidepressant treatment induces a decrease in 5-HT2AR density (PMID:25150943)
• Study furthers our understanding of positive allosteric modulation of the mGlu2 receptor and can contribute to improved future design of mGlu2 modulators. (PMID:25571949)
• this work offers new insights into the functioning of the mGlu2 receptor, which might contribute to the development of new and improved PAMs (PMID:26589404)
• Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. (PMID:26758213)
• The present data demonstrateD that a mechanism of group II mGluR-induced analgesia identified in rodent sensory neurons translates mechanistically to human sensory neurons (PMID:27218869)
• Studies support a role for NHERF-1 and NHERF-2 (Na+/H+ exchanger regulatory factors 1 and 2) in regulating the distribution of Group II metabotropic glutamate receptor (mGluRs) in the murine brain, while conversely the effects of the mGluR2/3 PDZ-binding motifs on receptor signaling are likely mediated by interactions with other PDZ scaffold proteins beyond the NHERF proteins. (PMID:28392297)
• mGlu2 receptors can play an influential role in reducing the probability of glutamate neurotransmitter release and potentially effect seizure activity. (PMID:29360159)
• data suggests that glutamatergic activity through GRM2 in cerebral cortex may differ with gender and suicide ideation. (PMID:30326345)
• This study investigates the role of unstructured loop (or “BC loop”) in Glutamate induced conformation of mGluR2 and its activation. mGluR2 without BC loop does not respond to Glutamate. (PMID:31706572)
• Conformational rearrangement during activation of a metabotropic glutamate receptor. (PMID:33398167)
• Structures of human mGlu2 and mGlu7 homo- and heterodimers. (PMID:34135509)
• Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4. (PMID:34135510)
• G-protein activation by a metabotropic glutamate receptor. (PMID:34194039)
• DNA methylation changes in genes involved in inflammation and depression in fibromyalgia: a pilot study. (PMID:34387961)
• Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state. (PMID:34521824)
• The crosstalk between 5-HT2AR and mGluR2 in schizophrenia. (PMID:36889432)
• Heterodimerization of Chemoreceptors TAS1R3 and mGlu2 in Human Blood Leukocytes. (PMID:37629122)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	grm2a	ENSDARG00000004150
danio_rerio	grm2b	ENSDARG00000007195
mus_musculus	Grm2	ENSMUSG00000023192
rattus_norvegicus	Grm2	ENSRNOG00000013171
drosophila_melanogaster	mtt	FBGN0050361
caenorhabditis_elegans		WBGENE00003232
caenorhabditis_elegans		WBGENE00021152

Paralogs (7): GRM6 (ENSG00000113262), GRM4 (ENSG00000124493), GRM1 (ENSG00000152822), GRM5 (ENSG00000168959), GRM8 (ENSG00000179603), GRM7 (ENSG00000196277), GRM3 (ENSG00000198822)

Protein

Protein identifiers

Metabotropic glutamate receptor 2 — Q14416 (reviewed: Q14416)

All UniProt accessions (4): C9JD41, C9JL63, Q14416, H7BXL3

UniProt curated annotations — full annotation on UniProt →

Function. Dimeric G protein-coupled receptor which is activated by the excitatory neurotransmitter L-glutamate. Plays critical roles in modulating synaptic transmission and neuronal excitability. Upon activation by glutamate, inhibits presynaptic calcium channels, reducing further glutamate release and dampening excitatory signaling. Mechanistically, ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization. (Microbial infection) Plays an important role in influenza virus internalization. (Microbial infection) Acts as a host entry factor for rabies virus that hijacks the endocytosis of GRM2 to enter cells. (Microbial infection) Acts as a host entry factor for SARS-CoV-2 that hijacks the endocytosis of GRM2 to enter cells.

Subunit / interactions. Forms heterodimers with GRM3 or GRM4. Interacts with TAMALIN. Interacts with HTR2A. (Microbial infection) Interacts with H5N6 virus protein HA. (Microbial infection) Interacts with rabies virus protein G. (Microbial infection) Interacts with SARS-CoV-2 virus spike protein S.

Subcellular location. Cell membrane. Synapse. Cell projection. Dendrite.

Tissue specificity. Detected in brain cortex (at protein level). Widely expressed in different regions of the adult brain as well as in fetal brain.

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

RefSeq proteins (3): NP_000830, NP_001336045, NP_001336046 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000162	GPCR_3_mtglu_rcpt	Family
IPR000337	GPCR_3	Family
IPR001458	GPCR_3_mGluR2	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 (130 total): strand 38, helix 31, turn 13, disulfide bond 10, topological domain 8, transmembrane region 7, binding site 7, glycosylation site 5, sequence conflict 5, mutagenesis site 3, signal peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

31 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4XAQ	X-RAY DIFFRACTION	2.21
4XAS	X-RAY DIFFRACTION	2.35
7EPE	X-RAY DIFFRACTION	2.5
5CNJ	X-RAY DIFFRACTION	2.65
5CNI	X-RAY DIFFRACTION	2.69
7EPF	X-RAY DIFFRACTION	2.7
5KZN	X-RAY DIFFRACTION	2.8
5KZQ	X-RAY DIFFRACTION	2.8
8JCU	ELECTRON MICROSCOPY	2.8
8JD2	ELECTRON MICROSCOPY	2.8
8JCY	ELECTRON MICROSCOPY	2.9
8JD4	ELECTRON MICROSCOPY	2.9
8JCW	ELECTRON MICROSCOPY	3
8JCX	ELECTRON MICROSCOPY	3
8JCZ	ELECTRON MICROSCOPY	3
7EPB	ELECTRON MICROSCOPY	3.1
7MTS	ELECTRON MICROSCOPY	3.2
7MTR	ELECTRON MICROSCOPY	3.3
8JD0	ELECTRON MICROSCOPY	3.3
8JD3	ELECTRON MICROSCOPY	3.3
8JCV	ELECTRON MICROSCOPY	3.4
7E9G	ELECTRON MICROSCOPY	3.5
7EPA	ELECTRON MICROSCOPY	3.6
8JD5	ELECTRON MICROSCOPY	3.6
7MTQ	ELECTRON MICROSCOPY	3.65
8JD1	ELECTRON MICROSCOPY	3.7
8WGB	ELECTRON MICROSCOPY	3.7
7EPD	ELECTRON MICROSCOPY	3.9
8WGD	ELECTRON MICROSCOPY	4.45
8WG9	ELECTRON MICROSCOPY	4.46

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14416-F1	86.17	0.58

Antibody-complex structures (SAbDab): 3 — 7E9G, 7EPB, 8JD5

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 (7): 57; 61; 145; 166; 168; 295; 377

Disulfide bonds (10): 50–92, 121, 234–518, 355–362, 400–407, 500–519, 504–522, 525–537, 540–553, 632–721

Glycosylation sites (5): 203, 286, 338, 402, 547

Mutagenesis-validated functional residues (3):

Position	Phenotype
677	impairs interaction with htr2a.
681	impairs interaction with htr2a.
685	impairs interaction with htr2a.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-418594	G alpha (i) signalling events
R-HSA-420499	Class C/3 (Metabotropic glutamate/pheromone receptors)

MSigDB gene sets: 159 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_GLUTAMATE_SECRETION, MODULE_274, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_COCAINE, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_ADULT_BEHAVIOR, MODULE_64, GOBP_G_PROTEIN_COUPLED_GLUTAMATE_RECEPTOR_SIGNALING_PATHWAY, GOBP_CELL_CELL_SIGNALING, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (21): negative regulation of adenylate cyclase activity (GO:0007194), G protein-coupled glutamate receptor signaling pathway (GO:0007216), chemical synaptic transmission (GO:0007268), gene expression (GO:0010467), glutamate secretion (GO:0014047), regulation of glutamate secretion (GO:0014048), regulation of dopamine secretion (GO:0014059), cellular response to stress (GO:0033554), behavioral response to nicotine (GO:0035095), response to cocaine (GO:0042220), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), regulation of synaptic transmission, glutamatergic (GO:0051966), long-term synaptic depression (GO:0060292), intracellular glutamate homeostasis (GO:0090461), presynaptic modulation of chemical synaptic transmission (GO:0099171), regulation of response to drug (GO:2001023), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway (GO:0007196), glutamate receptor signaling pathway (GO:0007215)

GO Molecular Function (6): group II metabotropic glutamate receptor activity (GO:0001641), G protein-coupled receptor activity (GO:0004930), calcium channel regulator activity (GO:0005246), glutamate receptor activity (GO:0008066), scaffold protein binding (GO:0097110), protein binding (GO:0005515)

GO Cellular Component (11): plasma membrane (GO:0005886), axon (GO:0030424), dendrite (GO:0030425), presynaptic membrane (GO:0042734), postsynaptic membrane (GO:0045211), astrocyte projection (GO:0097449), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell projection (GO:0042995), neuron projection (GO:0043005), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
GPCR downstream signalling	1
GPCR ligand binding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
cellular response to stimulus	2
modulation of chemical synaptic transmission	2
presynapse	2
adenylate cyclase inhibiting G protein-coupled glutamate receptor activity	2
transmembrane signaling receptor activity	2
neuron projection	2
synaptic membrane	2
cellular anatomical structure	2
adenylate cyclase activity	1
negative regulation of catalytic activity	1
regulation of adenylate cyclase activity	1
glutamate receptor signaling pathway	1
G protein-coupled glutamate receptor activity	1
anterograde trans-synaptic signaling	1
macromolecule biosynthetic process	1
dicarboxylic acid transport	1
acidic amino acid transport	1
secretion by cell	1
nitrogen compound transport	1
glutamate secretion	1
regulation of organic acid transport	1
regulation of amino acid transport	1
regulation of secretion by cell	1
dopamine secretion	1
regulation of catecholamine secretion	1
response to stress	1
adult behavior	1
response to nicotine	1
response to alkaloid	1
response to oxygen-containing compound	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
synaptic transmission, glutamatergic	1
regulation of synaptic plasticity	1
negative regulation of synaptic transmission	1
intracellular amino acid homeostasis	1
response to xenobiotic stimulus	1
regulation of response to stimulus	1

Protein interactions and networks

STRING

2163 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRM2	HTR2A	P28223	997
GRM2	GRIA1	P42261	965
GRM2	GRM4	Q14833	917
GRM2	GPRC5C	Q9NQ84	833
GRM2	GRIA4	P48058	832
GRM2	GPRC5A	Q8NFJ5	831
GRM2	HTR2B	P41595	780
GRM2	GRIK1	P39086	757
GRM2	CYP19A1	P11511	732
GRM2	GRIN2B	Q13224	687
GRM2	GRIN2A	Q12879	656
GRM2	GRIN3A	Q8TCU5	621
GRM2	SLC1A2	P43004	620
GRM2	GRIK3	Q13003	616
GRM2	BDNF	P23560	610

IntAct

88 interactions, top by confidence:

A	B	Type	Score
GNG2	GNB1	psi-mi:“MI:0915”(physical association)	0.910
GRM2	HTR2A	psi-mi:“MI:0915”(physical association)	0.650
HTR2A	GRM2	psi-mi:“MI:0407”(direct interaction)	0.650
GRM2	NAALADL2	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	GRM2	psi-mi:“MI:0915”(physical association)	0.560
NAALADL2	GRM2	psi-mi:“MI:0915”(physical association)	0.560
GRM2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
GRM2	CPLX4	psi-mi:“MI:0915”(physical association)	0.560
GRM2	MFSD14B	psi-mi:“MI:0915”(physical association)	0.560
GRM2	MGST3	psi-mi:“MI:0915”(physical association)	0.560
GRM2	TSPAN18	psi-mi:“MI:0915”(physical association)	0.560
BIK	GRM2	psi-mi:“MI:0915”(physical association)	0.560
GRM2	SLC38A1	psi-mi:“MI:0915”(physical association)	0.560
GRM2	TMEM237	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	GRM2	psi-mi:“MI:0915”(physical association)	0.560
PDZK1IP1	GRM2	psi-mi:“MI:0915”(physical association)	0.560
GRM2	CCDC107	psi-mi:“MI:0915”(physical association)	0.560
GRM2	ACBD5	psi-mi:“MI:0915”(physical association)	0.560
GRM2	MMGT1	psi-mi:“MI:0915”(physical association)	0.560
CLDN9	GRM2	psi-mi:“MI:0915”(physical association)	0.560
CYB5R3	GRM2	psi-mi:“MI:0915”(physical association)	0.560
STOM	GRM2	psi-mi:“MI:0915”(physical association)	0.560
GRM2	SLC30A8	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (381): UBQLN1 (Two-hybrid), NAALADL2 (Two-hybrid), GRIP1 (Reconstituted Complex), SDCBP (Reconstituted Complex), GRM2 (Two-hybrid), PIK3CD (Negative Genetic), LARS2 (Negative Genetic), PTGIR (Negative Genetic), SSTR5 (Negative Genetic), NPEPPS (Negative Genetic), GRM2 (Positive Genetic), GRM2 (Positive Genetic), GRM2 (Positive Genetic), GRM2 (Two-hybrid), GRM2 (Two-hybrid)

ESM2 similar proteins: B3DIG4, O00144, O57328, O57329, O70421, O75084, O93274, P18537, P26572, P27115, P27808, P31421, P58421, P97812, Q08463, Q08464, Q09325, Q13467, Q14332, Q14416, Q14623, Q14BI2, Q24760, Q498S8, Q5BL72, Q61090, Q61091, Q62226, Q63673, Q7TN37, Q8AVJ9, Q8BKG4, Q8CHL0, Q8K4C8, Q98938, Q9DEB5, Q9EQD0, Q9ESQ5, Q9H461, Q9I9M5

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

5 interactions.

A	Effect	B	Mechanism
“(1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid”	up-regulates	GRM2	“chemical activation”
“glutamic acid”	“up-regulates activity”	GRM2	“chemical activation”
GRM2	“up-regulates activity”	GNAS	binding
GRM2	up-regulates	Excitatory_synaptic_transmission
GRM2	“up-regulates quantity”	calcium(2+)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	106
Likely benign	6
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1294 predictions. Top by Δscore:

Variant	Effect	Δscore
3:51709431:CAGG:C	donor_loss	1.0000
3:51709433:GGT:G	donor_loss	1.0000
3:51712468:CCCA:C	acceptor_loss	1.0000
3:51712469:CCA:C	acceptor_loss	1.0000
3:51712470:CAGGT:C	acceptor_loss	1.0000
3:51712471:A:AG	acceptor_gain	1.0000
3:51712471:AGGT:A	acceptor_gain	1.0000
3:51712472:G:A	acceptor_loss	1.0000
3:51712472:G:GG	acceptor_gain	1.0000
3:51712472:GGT:G	acceptor_gain	1.0000
3:51712472:GGTG:G	acceptor_gain	1.0000
3:51713283:G:GT	donor_gain	1.0000
3:51713299:TC:T	donor_gain	1.0000
3:51713363:G:T	donor_gain	1.0000
3:51714108:GGT:G	donor_gain	1.0000
3:51715060:A:AG	acceptor_gain	1.0000
3:51715061:G:GA	acceptor_gain	1.0000
3:51715061:GC:G	acceptor_gain	1.0000
3:51715061:GCC:G	acceptor_gain	1.0000
3:51715061:GCCC:G	acceptor_gain	1.0000
3:51715061:GCCCC:G	acceptor_gain	1.0000
3:51717627:C:G	acceptor_gain	1.0000
3:51717630:A:AG	acceptor_gain	1.0000
3:51717632:C:A	acceptor_gain	1.0000
3:51717633:GCA:G	acceptor_loss	1.0000
3:51717634:CA:C	acceptor_loss	1.0000
3:51717635:A:T	acceptor_loss	1.0000
3:51717635:AG:A	acceptor_gain	1.0000
3:51717636:GG:G	acceptor_gain	1.0000
3:51717814:CAAG:C	donor_loss	1.0000

AlphaMissense

5650 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:51709426:C:A	S148Y	1.000
3:51709426:C:T	S148F	1.000
3:51712512:A:C	S164R	1.000
3:51712514:C:A	S164R	1.000
3:51712514:C:G	S164R	1.000
3:51712522:C:T	S167F	1.000
3:51712828:T:G	F269C	1.000
3:51712911:T:A	W297R	1.000
3:51712911:T:C	W297R	1.000
3:51715333:G:C	W520C	1.000
3:51715333:G:T	W520C	1.000
3:51716039:T:C	F756L	1.000
3:51716041:C:A	F756L	1.000
3:51716041:C:G	F756L	1.000
3:51716090:T:A	W773R	1.000
3:51716090:T:C	W773R	1.000
3:51717667:A:C	S799R	1.000
3:51717669:C:A	S799R	1.000
3:51717669:C:G	S799R	1.000
3:51709090:G:A	G36E	0.999
3:51709251:G:C	D90H	0.999
3:51709252:A:T	D90V	0.999
3:51709254:A:C	S91R	0.999
3:51709256:T:A	S91R	0.999
3:51709256:T:G	S91R	0.999
3:51709257:T:A	C92S	0.999
3:51709258:G:A	C92Y	0.999
3:51709258:G:C	C92S	0.999
3:51709259:C:G	C92W	0.999
3:51709279:T:C	L99P	0.999

dbSNP variants (sampled 300 via entrez): RS1000075741 (3:51712306 T>C), RS1000561474 (3:51707566 G>T), RS1000964258 (3:51710990 G>T), RS1001016069 (3:51714668 TTG>T), RS1001075427 (3:51710762 A>C), RS1001199603 (3:51713961 A>C), RS1001239540 (3:51713640 C>A), RS1001395195 (3:51706863 GA>G), RS1001539869 (3:51707333 C>A,T), RS1001634705 (3:51714423 C>T), RS1001750717 (3:51713960 C>A,T), RS1002396110 (3:51707915 C>A,G,T), RS1002631902 (3:51710221 C>T), RS1003030299 (3:51709979 T>G), RS1003405749 (3:51709896 C>T)

Disease associations

OMIM: gene MIM:604099 | 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 (2): CHEMBL4630758 (PROTEIN COMPLEX), CHEMBL5137 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 929,958 (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
CHEMBL3337527	JNJ-40411813	2	84
CHEMBL8759	EGLUMETAD	2	81
CHEMBL375611	LY404039	1	37

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 (52 total), top 25:

Ligand	Action	Affinity	Parameter
MGS0028	Full agonist	9.2	pKi
[3H]LY341495	Antagonist	8.8	pKd
RO5488608	Negative	8.72	pKi
MGS0039	Antagonist	8.7	pKi
LY341495	Antagonist	8.6	pKi
[3H]2,2,2-TEMPS	Positive	8.38	pKd
JNJ-46281222	Positive	8.33	pKi
RO4988546	Negative	8.26	pIC50
MNI-136	Negative	8.06	pIC50
MNI-135	Negative	7.98	pIC50
[3H]JNJ-40068782	Positive	7.92	pKd
LY379268	Full agonist	7.9	pKi
MNI-137	Negative	7.9	pIC50
Ro4491533	Negative	7.85	pIC50
2,2,2-TEMPS	Positive	7.85	pEC50
JNJ-40068782	Positive	7.82	pEC50
JNJ-42153605	Positive	7.77	pEC50
[3H]eglumegad	Full agonist	7.7	pKd
THIIC	Positive	7.65	pEC50
compound 14a [PMID: 18812259]	Positive	7.6	pEC50
cyPPTS	Positive	7.6	pEC50
compound 14c [PMID: 18812259]	Positive	7.5	pEC50
compound 19 [PMID: 18812259]	Positive	7.2	pEC50
GSK1331258	Positive	7.1	pEC50
compound 34 [PMID: 20409708]	Positive	7.08	pEC50

Binding affinities (BindingDB)

945 measured of 1024 human assays (1055 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-(cyclopropylmethyl)-7-[4-(3,6-difluoro-2-methoxyphenyl)piperidin-1-yl]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine	EC50	0.2 nM	US-9682980: Positive allosteric modulators of mGluR2
(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
7-[4-(3,6-difluoro-2-methoxyphenyl)piperidin-1-yl]-3-(2,2,2-trifluoroethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine	EC50	0.4 nM	US-9682980: Positive allosteric modulators of mGluR2
(6R)-1-(2,6-dimethyl-4-pyridinyl)-3-[3-ethoxy-4-(trifluoromethyl)phenyl]-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	1.1 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-[3-ethoxy-4-(trifluoromethyl)phenyl]-6-methyl-1-(2-methyl-4-pyridinyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	1.7 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6S)-1-(2,6-dimethyl-4-pyridinyl)-3-(4-ethoxy-3-methylphenyl)-6-(fluoromethyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	1.7 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6S)-3-(3-chloro-4-cyclopropyloxyphenyl)-1-(2,6-dimethyl-4-pyridinyl)-6-(fluoromethyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	1.8 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6S)-1-(2,6-dimethyl-4-pyridinyl)-6-(fluoromethyl)-3-(3-methyl-4-propan-2-yloxyphenyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	1.8 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-6-methyl-1-(2-methyl-4-pyridinyl)-3-[3-methyl-4-(trifluoromethoxy)phenyl]-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	1.9 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-[4-(difluoromethoxy)-3-(fluoromethyl)phenyl]-1-(2,6-dimethyl-4-pyridinyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	1.9 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
8-chloro-7-[4-(2-fluoro-6-methoxyphenyl)piperidin-1-yl]-3-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-b]pyridazine	EC50	2 nM	US-9682980: Positive allosteric modulators of mGluR2
8-chloro-3-(cyclopropylmethyl)-7-[4-[2-(difluoromethoxy)-3,6-difluorophenyl]piperidin-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine	EC50	2 nM	US-9682980: Positive allosteric modulators of mGluR2
(6S)-3-[3-chloro-4-(difluoromethoxy)phenyl]-1-(2,6-dimethyl-4-pyridinyl)-6-(fluoromethyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6S)-6-(fluoromethyl)-1-[2-(fluoromethyl)-6-methyl-4-pyridinyl]-3-[3-methoxy-4-(trifluoromethyl)phenyl]-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2.4 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-1-(2,6-dimethyl-4-pyridinyl)-3-[3-(fluoromethyl)-4-(trifluoromethoxy)phenyl]-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2.4 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-1-(2,6-dimethyl-4-pyridinyl)-6-methyl-3-(3-methyl-4-propan-2-yloxyphenyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2.4 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-[3-(fluoromethyl)-4-(trifluoromethoxy)phenyl]-6-methyl-1-(2-methyl-4-pyridinyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2.5 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6S)-1-(2,6-dimethyl-4-pyridinyl)-6-(fluoromethyl)-3-[3-methoxy-4-(trifluoromethoxy)phenyl]-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2.7 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-(3-chloro-4-propan-2-yloxyphenyl)-1-(2,6-dimethyl-4-pyridinyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2.7 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-[3-chloro-4-(difluoromethoxy)phenyl]-1-(2,6-dimethyl-4-pyridinyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2.8 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-(3-chloro-4-ethoxyphenyl)-1-(2,6-dimethyl-4-pyridinyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2.8 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-[4-(difluoromethoxy)-3-(fluoromethyl)phenyl]-6-methyl-1-(2-methyl-4-pyridinyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2.9 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-1-(2,6-dimethyl-4-pyridinyl)-3-(4-ethoxy-3-methylphenyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	2.9 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine	EC50	3 nM	US-9682980: Positive allosteric modulators of mGluR2
8-chloro-3-(cyclopropylmethyl)-7-[4-(2-fluoro-6-methoxyphenyl)piperidin-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine	EC50	3 nM	US-9682980: Positive allosteric modulators of mGluR2
8-chloro-7-[4-[2-(difluoromethoxy)-3,6-difluorophenyl]piperidin-1-yl]-3-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-b]pyridazine	EC50	3 nM	US-9682980: Positive allosteric modulators of mGluR2
3-(cyclopropylmethyl)-7-[4-(2-fluoro-6-methoxyphenyl)piperidin-1-yl]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine	EC50	3 nM	US-9682980: Positive allosteric modulators of mGluR2
(6R)-3-(3-chloro-4-cyclopropyloxyphenyl)-1-(2,6-dimethyl-4-pyridinyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	3 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-[3-chloro-4-(trifluoromethoxy)phenyl]-6-methyl-1-(2-methyl-4-pyridinyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	3 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-[3-(cyclobutylmethoxy)-4-fluorophenyl]-1-(2,6-dimethyl-4-pyridinyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	3.1 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-1-(2,6-dimethyl-4-pyridinyl)-3-[3-methoxy-4-(trifluoromethoxy)phenyl]-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	3.2 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-(4-cyclopropyloxy-3-methylphenyl)-1-(2,6-dimethyl-4-pyridinyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	3.4 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6S)-3-[4-(difluoromethoxy)-3-methylphenyl]-1-(2,6-dimethyl-4-pyridinyl)-6-(fluoromethyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	3.5 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
5-[(6S)-1-(2,6-dimethyl-4-pyridinyl)-6-(fluoromethyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzonitrile	IC50	3.7 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6S)-6-(fluoromethyl)-3-[3-methoxy-4-(trifluoromethoxy)phenyl]-1-(2-methyl-4-pyridinyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	3.8 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6S)-1-(2,6-dimethyl-4-pyridinyl)-6-(fluoromethyl)-3-[3-methoxy-4-(trifluoromethyl)phenyl]-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	3.8 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-3-(4-chloro-3-methoxyphenyl)-6-ethyl-1-(2-methyl-4-pyridinyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	3.8 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
5-[(6S)-6-(fluoromethyl)-1-(2-methyl-4-pyridinyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzonitrile	IC50	3.8 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-1-(2,6-dimethyl-4-pyridinyl)-3-(3-ethoxy-4-methylphenyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	3.9 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
8-chloro-3-(cyclopropylmethyl)-7-[4-(2-fluorophenyl)piperidin-1-yl]-[1,2,4]triazolo[4,3-c]pyrimidine	EC50	4 nM	US-9682980: Positive allosteric modulators of mGluR2
2-[1-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-7-yl]piperidin-4-yl]benzonitrile	EC50	4 nM	US-9682980: Positive allosteric modulators of mGluR2
3-(cyclopropylmethyl)-7-[4-(2-fluorophenyl)piperidin-1-yl]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine	EC50	4 nM	US-9682980: Positive allosteric modulators of mGluR2
4-(3-fluoro-4-methoxyphenyl)-7-[2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2-carboxamide	IC50	4 nM	US-9278960: Quinoline carboxamide and quinoline carbonitrile derivatives as mGluR2-negative allosteric modulators, compositions, and their use
(6S)-1-(2,6-dimethyl-4-pyridinyl)-6-(fluoromethyl)-3-[3-methyl-4-(trifluoromethoxy)phenyl]-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	4 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-1-[2-(fluoromethyl)-6-methyl-4-pyridinyl]-6-methyl-3-[3-methyl-4-(trifluoromethoxy)phenyl]-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	4 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6S)-3-(4-cyclopropyloxy-3-methylphenyl)-1-(2,6-dimethyl-4-pyridinyl)-6-(fluoromethyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	4.1 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6S)-6-(fluoromethyl)-3-[3-methoxy-4-(trifluoromethyl)phenyl]-1-(2-methyl-4-pyridinyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	4.1 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-1-(2,6-dimethyl-4-pyridinyl)-3-[3-methoxy-4-(trifluoromethyl)phenyl]-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	4.2 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
(6R)-1-(2,6-dimethyl-4-pyridinyl)-3-(4-ethyl-3-methoxyphenyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine	IC50	4.2 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative
5-[(6R)-1-(2,6-dimethyl-4-pyridinyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzonitrile	IC50	4.2 nM	US-9458176: Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative

ChEMBL bioactivities

3056 potent at pChembl≥5 of 3209 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.05	EC50	0.089	nM	CHEMBL218710
9.80	EC50	0.16	nM	CHEMBL2381640
9.72	Ki	0.19	nM	CHEMBL3955188
9.70	EC50	0.2	nM	CHEMBL5950884
9.49	Ki	0.32	nM	CHEMBL5405921
9.40	EC50	0.4	nM	CHEMBL3884532
9.40	EC50	0.4	nM	CHEMBL3883435
9.40	EC50	0.4	nM	CHEMBL6037536
9.34	Ki	0.46	nM	CHEMBL3945590
9.30	EC50	0.5	nM	CHEMBL3884187
9.25	EC50	0.56	nM	CHEMBL2381652
9.24	EC50	0.57	nM	CHEMBL121053
9.24	EC50	0.58	nM	CHEMBL3616857
9.19	EC50	0.65	nM	CHEMBL3616856
9.15	Ki	0.7	nM	CHEMBL5409898
9.13	Ki	0.74	nM	CHEMBL5418895
9.11	Ki	0.78	nM	CHEMBL5429000
9.10	Ki	0.8	nM	CHEMBL5394450
9.05	Ki	0.8913	nM	CHEMBL4063313
9.02	Ki	0.96	nM	CHEMBL5435246
9.00	Ki	1	nM	CHEMBL3885379
9.00	Kd	1	nM	CHEMBL4074664
9.00	Ki	1	nM	CHEMBL5429261
8.96	IC50	1.1	nM	CHEMBL4108184
8.96	Kd	1.1	nM	CHEMBL4087196
8.96	Ki	1.1	nM	CHEMBL3979547
8.96	Ki	1.1	nM	CHEMBL5436775
8.95	EC50	1.122	nM	CHEMBL4063313
8.92	Kd	1.2	nM	CHEMBL4073628
8.89	EC50	1.3	nM	CHEMBL2381641
8.89	EC50	1.3	nM	CHEMBL3884636
8.85	EC50	1.4	nM	CHEMBL3885379
8.85	Ki	1.4	nM	CHEMBL3950572
8.82	Kd	1.5	nM	CHEMBL4063313
8.82	Ki	1.514	nM	CHEMBL4101354
8.82	Ki	1.5	nM	CHEMBL5405655
8.77	EC50	1.7	nM	CHEMBL3883634
8.77	IC50	1.7	nM	CHEMBL4112479
8.77	IC50	1.7	nM	CHEMBL4109246
8.77	Ki	1.7	nM	CHEMBL5410262
8.74	EC50	1.8	nM	CHEMBL3884094
8.74	IC50	1.8	nM	CHEMBL4108743
8.74	IC50	1.8	nM	CHEMBL4110543
8.74	Ki	1.8	nM	CHEMBL3892073
8.74	IC50	1.8	nM	CHEMBL5596190
8.72	IC50	1.9	nM	CHEMBL4109319
8.72	IC50	1.9	nM	CHEMBL4112624
8.72	Ki	1.905	nM	CHEMBL4077609
8.71	Ki	1.95	nM	CHEMBL4075258
8.70	IC50	2	nM	CHEMBL4107872

PubChem BioAssay actives

1492 with measured affinity, of 2898 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
(1R,4S,5S,6S)-4-amino-2-oxo-2lambda4-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid	275489: Agonist activity at human mGluR2 assessed as effect on cAMP production in RGT cells	ec50	0.0001	uM
4-(2-fluoro-4-methoxyphenyl)-7-[2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0002	uM
(1S,2S,5R,6R)-2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid	748171: Agonist activity at human mGlu2 receptor expressed in golden Syrian hamster AV12 cells coexpressing EAAT1 after 20 mins by HTRF assay	ec50	0.0002	uM
7-[2-(2-cyanopyrimidin-5-yl)ethyl]-4-(4-fluorophenyl)quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0003	uM
3-(cyclopropylmethyl)-7-(4-phenylcyclohexyl)oxy-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1336493: Positive allosteric modulation of human mGlu2 receptor expressed in HEK293 cells coexpressing rat glutamate transporter assessed as inhibition of forskolin-stimulated cAMP production measured after 30 mins in presence of orthosteric antagonist LY341495 by FLIPR assay	ec50	0.0004	uM
3-(cyclopropylmethyl)-7-[3-(4-fluorophenyl)cyclobutyl]oxy-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1336493: Positive allosteric modulation of human mGlu2 receptor expressed in HEK293 cells coexpressing rat glutamate transporter assessed as inhibition of forskolin-stimulated cAMP production measured after 30 mins in presence of orthosteric antagonist LY341495 by FLIPR assay	ec50	0.0004	uM
3-(cyclopropylmethyl)-7-(3-phenylcyclobutyl)oxy-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1336493: Positive allosteric modulation of human mGlu2 receptor expressed in HEK293 cells coexpressing rat glutamate transporter assessed as inhibition of forskolin-stimulated cAMP production measured after 30 mins in presence of orthosteric antagonist LY341495 by FLIPR assay	ec50	0.0005	uM
4-(3-fluoro-4-methoxyphenyl)-7-[2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0005	uM
(1R,2S,4R,5R,6R)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid	748171: Agonist activity at human mGlu2 receptor expressed in golden Syrian hamster AV12 cells coexpressing EAAT1 after 20 mins by HTRF assay	ec50	0.0006	uM
(1R,2S,4S,5R,6R)-2-amino-4-[[5-(difluoromethyl)-1H-1,2,4-triazol-3-yl]sulfanyl]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid	1247515: Agonist activity at human recombinant mGlu2 receptor expressed in AV12 cells assessed as inhibition of forskolin-stimulated cAMP production after 1 hr by fluorescence assay	ec50	0.0006	uM
(1R,2S,4S,5R,6R)-2-amino-4-[[5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl]sulfanyl]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid	1247515: Agonist activity at human recombinant mGlu2 receptor expressed in AV12 cells assessed as inhibition of forskolin-stimulated cAMP production after 1 hr by fluorescence assay	ec50	0.0006	uM
(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid	705582: Agonist activity at mGLUR2 expressed in CHO cells	ec50	0.0006	uM
7-[2-[6-(fluoromethyl)-3-pyridinyl]ethyl]-4-(4-fluorophenyl)quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0007	uM
4-(2-fluoro-4-methylphenyl)-7-[2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0007	uM
4-(4-fluorophenyl)-7-[2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0008	uM
4-(4-fluorophenyl)-7-[2-(2-fluoropyrimidin-5-yl)ethyl]quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0008	uM
4-[2-chloro-4-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]anilino]-1-cyclopropylcyclohexan-1-ol	1458074: Displacement of [3H]-JNJ46281222 from human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes after 60 mins by microbeta counting analysis	ki	0.0009	uM
7-[[(1S,2S)-2-(4-chlorophenyl)cyclopropyl]methoxy]-3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1336499: Displacement of [3H]-JNJ-40068782 from human mGlu2 receptor expressed in HEK293 cell membranes coexpressing rat glutamate transporter measured after 30 mins in presence of orthosteric antagonist LY341495 by liquid scintillation counting method	ki	0.0010	uM
7-[2-(6-cyano-3-pyridinyl)ethyl]-4-(4-fluorophenyl)quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0010	uM
4-(4-fluorophenyl)-7-[2-(6-fluoro-3-pyridinyl)ethyl]quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0010	uM
8-chloro-7-[3-chloro-4-[(2,6-dimethyl-3-pyridinyl)oxy]phenyl]-3-(cyclopropylmethyl)-[1,2,4]triazolo[4,3-a]pyridine	1458071: Binding affinity to human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes by scintillation proximity assay	kd	0.0010	uM
4-(4-fluorophenyl)-7-[2-(6-methyl-3-pyridinyl)ethyl]quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0011	uM
N-cyclopropyl-4-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]-2-fluoroaniline	1458071: Binding affinity to human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes by scintillation proximity assay	kd	0.0011	uM
4-(4-fluorophenyl)-7-(2-pyridin-3-ylethyl)quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0011	uM
2-chloro-N-cyclopropyl-4-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]aniline	1458071: Binding affinity to human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes by scintillation proximity assay	kd	0.0012	uM
7-[[2-(4-chlorophenyl)cyclopropyl]methoxy]-3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1336493: Positive allosteric modulation of human mGlu2 receptor expressed in HEK293 cells coexpressing rat glutamate transporter assessed as inhibition of forskolin-stimulated cAMP production measured after 30 mins in presence of orthosteric antagonist LY341495 by FLIPR assay	ec50	0.0013	uM
(1S,2S,5R,6S)-2-amino-4-methylidenebicyclo[3.1.0]hexane-2,6-dicarboxylic acid	748171: Agonist activity at human mGlu2 receptor expressed in golden Syrian hamster AV12 cells coexpressing EAAT1 after 20 mins by HTRF assay	ec50	0.0013	uM
4-(4-fluorophenyl)-7-(2-pyrimidin-5-ylethyl)quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0014	uM
7-[2-[2-(fluoromethyl)pyrimidin-5-yl]ethyl]-4-(4-fluorophenyl)quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0015	uM
7-[3-chloro-4-[(2,6-dimethyl-3-pyridinyl)oxy]phenyl]-3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1458074: Displacement of [3H]-JNJ46281222 from human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes after 60 mins by microbeta counting analysis	ki	0.0015	uM
3-(cyclopropylmethyl)-7-[[2-(4-fluorophenyl)cyclopropyl]methoxy]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1336493: Positive allosteric modulation of human mGlu2 receptor expressed in HEK293 cells coexpressing rat glutamate transporter assessed as inhibition of forskolin-stimulated cAMP production measured after 30 mins in presence of orthosteric antagonist LY341495 by FLIPR assay	ec50	0.0017	uM
4-[4-(fluoromethyl)phenyl]-7-[2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0017	uM
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-3-(2-methyl-4-pyridinyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one	2123571: Negative allosteric modulator activity at human mGluR2 receptor expressed in CHO cell membrane measured by microplate scintillation and luminescence counting based [35S]GTPgammaS binding assay	ic50	0.0018	uM
3-(cyclopropylmethyl)-7-[(1-phenylcyclohexyl)methoxy]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1336493: Positive allosteric modulation of human mGlu2 receptor expressed in HEK293 cells coexpressing rat glutamate transporter assessed as inhibition of forskolin-stimulated cAMP production measured after 30 mins in presence of orthosteric antagonist LY341495 by FLIPR assay	ec50	0.0018	uM
7-[(2,5-dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0018	uM
8-chloro-3-(cyclopropylmethyl)-7-[4-[(2,6-dimethyl-3-pyridinyl)oxy]-3-fluorophenyl]-[1,2,4]triazolo[4,3-a]pyridine	1458074: Displacement of [3H]-JNJ46281222 from human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes after 60 mins by microbeta counting analysis	ki	0.0019	uM
4-[2-chloro-4-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]phenoxy]cyclohexan-1-ol	1458074: Displacement of [3H]-JNJ46281222 from human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes after 60 mins by microbeta counting analysis	ki	0.0019	uM
4-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]-N-[(6-methoxy-3-pyridinyl)methyl]aniline	1458071: Binding affinity to human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes by scintillation proximity assay	kd	0.0020	uM
4-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]-2-fluoro-N-[(6-methoxy-3-pyridinyl)methyl]aniline	1458074: Displacement of [3H]-JNJ46281222 from human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes after 60 mins by microbeta counting analysis	ki	0.0020	uM
7-[4-[(2,6-dimethyl-3-pyridinyl)oxy]-3-fluorophenyl]-3-(ethoxymethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1458071: Binding affinity to human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes by scintillation proximity assay	kd	0.0021	uM
4-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]-2-fluoro-N-propan-2-ylaniline	1458071: Binding affinity to human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes by scintillation proximity assay	kd	0.0022	uM
4-[2-chloro-4-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]anilino]cyclohexan-1-ol	1458074: Displacement of [3H]-JNJ46281222 from human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes after 60 mins by microbeta counting analysis	ki	0.0022	uM
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-dichlorophenyl)methoxy]-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid	705388: Binding affinity to mGLUR2	ki	0.0022	uM
3-(cyclopropylmethyl)-7-[4-[(2,6-dimethyl-3-pyridinyl)oxy]-3-fluorophenyl]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1458071: Binding affinity to human metabotropic glutamate receptor 2 expressed in CHOK1 cell membranes by scintillation proximity assay	kd	0.0025	uM
3-(cyclopropylmethyl)-7-[(3-methyl-3-phenylpiperidin-1-yl)methyl]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	1319669: Positive allosteric modulation of human mGlu2 receptor expressed in CHO cell membranes assessed as potentiation of glutamate-induced effect incubated for 30 mins prior to [35S]GTPgamma addition measured after 30 mins by scintillation counting method	ec50	0.0026	uM
4-(4-methoxyphenyl)-7-[2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2-carboxamide	1975662: Binding affinity to human mGluR2 expressed in cell membrane incubated for 1 hr in presence of tritium labeled [3H]-7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide by competitive radioligand binding assay	ki	0.0026	uM
(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid	108680: Inhibition of forskolin stimulated cAMP production in RGT cells expressing recombinant human Metabotropic glutamate receptor 2	ec50	0.0027	uM
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-3-[2-(methylamino)-4-pyridinyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one	2123571: Negative allosteric modulator activity at human mGluR2 receptor expressed in CHO cell membrane measured by microplate scintillation and luminescence counting based [35S]GTPgammaS binding assay	ic50	0.0028	uM
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-3-(2,6-dimethyl-4-pyridinyl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one	2123571: Negative allosteric modulator activity at human mGluR2 receptor expressed in CHO cell membrane measured by microplate scintillation and luminescence counting based [35S]GTPgammaS binding assay	ic50	0.0029	uM
trans-(1S,2S)-2-[(1S)-1-amino-1-carboxy-2-(9H-xanthen-9-yl)ethyl]cyclopropane-1-carboxylic acid	328245: Displacement of [3H]-MGS0008 from mGluR2 expressed in CHO cells	ic50	0.0029	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
terbufos	increases methylation	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
(+)-JQ1 compound	increases expression	1
Acetylcysteine	increases activity	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carbamazepine	affects expression	1
Fonofos	increases methylation	1
Methamphetamine	increases response to substance	1
Parathion	increases methylation	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Triclosan	increases expression	1
Aflatoxin B1	decreases expression	1
Acrylamide	decreases expression	1
Permethrin	increases expression	1

ChEMBL screening assays

415 unique, capped per target: 219 functional, 187 binding, 9 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4627010	Functional	Agonist activity at human 5HT2A/mGlu2 receptor expressed in HEK293 cells co-expressing Gqo5 assessed as increase in intracellular Ca2+ mobilization incubated for 1 hr by Fluo-4 dye based fluorescence assay	Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT2A/mGlu2 Receptor Complex. — J Med Chem
CHEMBL4627018	Binding	Displacement of [3H]-ketanserin from human 5HT2A/mGlu2 receptor expressed in HEK293 cell membranes incubated for 2 hrs by scintillation counting method	Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT2A/mGlu2 Receptor Complex. — J Med Chem
CHEMBL3619435	Unclassified	Ratio of EC50 for human recombinant mGlu2 receptor by FLIPR assay to drug level in Sprague-Dawley rat cerebrospinal fluid at 1 mg/kg, ip after 0.5 hrs	Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_C0ST	ACTOne GRM2	Transformed cell line	Female
CVCL_D9FX	Ubigene HEK293 GRM2 KO	Transformed cell line	Female
CVCL_H445	CHO-K1/GRM2/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KS48	MultiScreen HEK293T mGluR2	Transformed cell line	Female
CVCL_KV32	cAMP Hunter CHO-K1 GRM2 Gi	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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