GRIN1

Summary

GRIN1 (glutamate ionotropic receptor NMDA type subunit 1, HGNC:4584) is a protein-coding gene on chromosome 9q34.3, encoding Glutamate receptor ionotropic, NMDA 1 (Q05586). Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).

The protein encoded by this gene is a critical subunit of N-methyl-D-aspartate receptors, members of the glutamate receptor channel superfamily which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits play a key role in the plasticity of synapses, which is believed to underlie memory and learning. Cell-specific factors are thought to control expression of different isoforms, possibly contributing to the functional diversity of the subunits. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 2902 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 1,267 total — 55 pathogenic, 54 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 39 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_007327

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4584
Approved symbol	GRIN1
Name	glutamate ionotropic receptor NMDA type subunit 1
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Aliases	GluN1, NR1
Ensembl gene	ENSG00000176884
Ensembl biotype	protein_coding
OMIM	138249
Entrez	2902

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 7 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000350902, ENST00000371546, ENST00000371550, ENST00000371553, ENST00000371555, ENST00000371559, ENST00000371560, ENST00000371561, ENST00000460273, ENST00000462584, ENST00000471122, ENST00000473811, ENST00000485413, ENST00000675064, ENST00000675295, ENST00000675885, ENST00000676396

RefSeq mRNA: 5 — MANE Select: NM_007327 NM_000832, NM_001185090, NM_001185091, NM_007327, NM_021569

CCDS: CCDS43910, CCDS55354, CCDS55355, CCDS7031, CCDS7032

Canonical transcript exons

ENST00000371561 — 20 exons

Exon	Start	End
ENSE00001273328	137165186	137165296
ENSE00001273335	137163759	137163904
ENSE00001273419	137156863	137157037
ENSE00003488923	137142013	137142147
ENSE00003511594	137162846	137163003
ENSE00003540068	137162591	137162739
ENSE00003547479	137158621	137158704
ENSE00003548246	137149009	137149109
ENSE00003572647	137163559	137163668
ENSE00003572985	137161289	137161416
ENSE00003576691	137163169	137163330
ENSE00003609791	137162172	137162290
ENSE00003622678	137162404	137162516
ENSE00003642805	137156669	137156790
ENSE00003648634	137161924	137162088
ENSE00003649829	137145726	137145902
ENSE00003659319	137161056	137161197
ENSE00003718745	137158379	137158523
ENSE00003750775	137167411	137168756
ENSE00003995993	137139154	137139744

Expression profiles

Bgee: expression breadth ubiquitous, 215 present calls, max score 99.04.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 25.0129 / max 1545.2880, expressed in 142 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
99654	21.1177	113
99653	1.9456	97
99650	1.2617	101
99655	0.1878	73
205695	0.1432	65
99652	0.1264	63
99651	0.1120	56
205694	0.0452	22
99656	0.0442	33
99659	0.0290	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.04	gold quality
right frontal lobe	UBERON:0002810	98.87	gold quality
cerebellar hemisphere	UBERON:0002245	98.67	gold quality
cerebellar cortex	UBERON:0002129	98.61	gold quality
anterior cingulate cortex	UBERON:0009835	97.66	gold quality
cingulate cortex	UBERON:0003027	97.61	gold quality
nucleus accumbens	UBERON:0001882	97.48	gold quality
prefrontal cortex	UBERON:0000451	96.88	gold quality
cerebellum	UBERON:0002037	96.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.27	gold quality
putamen	UBERON:0001874	96.20	gold quality
amygdala	UBERON:0001876	96.15	gold quality
cortical plate	UBERON:0005343	96.06	gold quality
caudate nucleus	UBERON:0001873	95.96	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.79	gold quality
frontal pole	UBERON:0002795	95.75	gold quality
middle frontal gyrus	UBERON:0002702	95.52	gold quality
paraflocculus	UBERON:0005351	95.49	gold quality
frontal cortex	UBERON:0001870	95.12	gold quality
neocortex	UBERON:0001950	94.85	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.80	gold quality
telencephalon	UBERON:0001893	93.44	gold quality
hypothalamus	UBERON:0001898	93.24	gold quality
cerebral cortex	UBERON:0000956	92.81	gold quality
vena cava	UBERON:0004087	91.91	silver quality
Ammon’s horn	UBERON:0001954	91.19	gold quality
temporal lobe	UBERON:0001871	90.98	gold quality
cerebellar vermis	UBERON:0004720	90.45	gold quality
brain	UBERON:0000955	90.41	gold quality
forebrain	UBERON:0001890	90.16	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-30	yes	1785.15
E-GEOD-84465	yes	6.60
E-GEOD-137537	yes	5.93
E-CURD-53	no	16.26
E-ANND-3	no	1.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

44 targeting GRIN1, 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-3120-5P	100.00	65.56	965
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-5094	98.63	67.11	1062
HSA-MIR-3180	98.46	64.68	348
HSA-MIR-3180-3P	98.46	64.68	348
HSA-MIR-6816-5P	98.46	64.35	364

Literature-anchored findings (GeneRIF, showing 40)

• the rapidly and slowly degrading pools mainly consisted of the NR1 splice variants NR1-4a and NR1-2a. deglycosylation by endoglycosidase H indicated the presence of an immature form of NR1 that was retained in the endoplasmic reticulum. (PMID:11803122)
• molecular interaction between PSD-95 and nmda receptors: the effct of the NR1 splice variant on channel gating. (PMID:12068077)
• Alteration of branch site consensus sequence and enhanced pre-mRNA splicing of an NMDAR1 intron not associated with schizophrenia. (PMID:12210277)
• involvement of the GRIN1 in the pathogenesis of bipolar disorder (PMID:12610658)
• Tested the association of two silent polymorphisms, a G/C substitution localized on the 5’ UTR and an A/G substitution localized in exon 6, with schizophrenia and found no significant results. Haplotype analyses showed a borderline significant result. (PMID:12707933)
• human cerebral endothelial cells express the message and protein for NMDA receptors. (PMID:12893641)
• Variants in NMDAR genes are associated with alcoholism and related traits. (PMID:14573320)
• SIDS infants had increased mRNA in 6 nuclei of the mid-medulla, while protein was increased in the dorsal motor nucleus of the vagus (p = 0.04) and decreased in the nucleus of the spinal trigeminal tract (p = 0.03). (PMID:14575242)
• disulfide bridging and structural integrity within the NR1 N-terminal domain is requisite for cell surface N-methyl-D-aspartate receptor expression (PMID:14732708)
• the NR1 promoter is positively regulated by NF-kappaB site during neuronal differentiation by interacting with Sp3/Sp1 (PMID:14970236)
• A significant decrease in the phosphorylation level at serine 897 (S897) of the NMDA receptor type 1 (NR1) subunit was found in brains from patients with schizophrenia (PMID:14973229)
• Absolute levels of the eight NR1 transcripts by quantitative internally standardized RT-PCR assay were measured; expression was strongly attenuated in susceptible regions of Alzheimer’s disease brain (PMID:15030408)
• Increased coassembly of NR1 and NR2B with PSD-95 may underlie one of the cellular mechanisms that contributes to in situ increased hyperexcitability, leading to seizure generation in focal cortical dysplasia. (PMID:15030493)
• NMDA receptor may play a role in the regulation of keratinocyte growth and differentiation (PMID:15265015)
• NMDA receptors are expressed in human epidermis under physiological conditions especially in stratum granulosum. Their reduced expression within parakeratotic epidermis in psoriasis vulgaris may be evidence of impaired intracellular calcium influx. (PMID:15338240)
• arginine 260 is necessary for both tPA-induced cleavage of the ATD of NR1 and tPA-induced potentiation of NMDA receptor signaling (PMID:15448144)
• A tendency to a decrease in the density of the NR1 upper band below control values is found in superior temporal cortex of bipolar and depressed patients, but not schizophrenics. (PMID:15531111)
• Genes for the NMDAR1 subunit is not frequently involved in the development of schizophrenia in the German population. (PMID:15564900)
• the combined effects of the polymorphisms in the GRIN1 and GRIN2B genes might be involved in the etiology of schizophrenia. (PMID:15841096)
• the conformation of NR1 subunit homodimers is affected by the partner NR2 subunits during the formation of heteromeric receptor complexes (PMID:15888440)
• These results suggest that NR1 may play a role in carcinogenicity and cell death associated with one-electron reductions. (PMID:16140270)
• Significant reductions were found in relative NMDA receptor binding in left hippocampal medication-free, but not antipsychotic-treated, schizophrenic patients. (PMID:16189506)
• These results demonstrate that human T lymphocytes express the NR1 subunit of NMDA receptors, which are functionally active in controlling cell activation. (PMID:16289038)
• ApoEr2 can form a multiprotein complex with NMDA receptor subunits and PSD95 (PMID:16332682)
• NR3 nmda receptor subunits induce plasticity in NR1 with respect to subunit assembly and ligand binding/channel coupling that is unique among ligand-gated ion channel subunits. (PMID:17047094)
• the three amino acid tail following the TM4 region of the N-methyl-D-aspartate receptor (NR) 2 subunits is sufficient to overcome endoplasmic reticulum retention of NR1-1a subunit (PMID:17255096)
• Data show that SNPs in GRIN1 gene were related to the bipolar disorder. The results confirm that the GRIN1 gene confers susceptibility to bipolar disorder. (PMID:17284422)
• The results clearly indicate that D1R-modulated NR1a/NR2B receptor function depends on PSD-95 and is subjected to the regulation of PKA and PKC. (PMID:17506933)
• Significant associations in single-marker and haplotype-based analyses pf variants and schiophrenia with depressive symptoms. (PMID:17728671)
• the synaptic NMDA receptor extracellular signal-regulated kinase activation pathway is coupled to both NR2A and NR2B containing receptors (PMID:18068304)
• deletion of the C terminus of the mGlu5a receptor abolishes both its interaction with the NMDA receptor and reciprocal inhibition of the receptors (PMID:18182392)
• NR1 expression begins low prenatally, peaks in adolescence, yet remains high throughout life, suggesting lifelong importance of NMDAR function (PMID:18296432)
• MMP-7 cleaves the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor to generate an N-terminal fragment of approximately 65 kDa (PMID:18644839)
• NR1-1a (D732E)/NR2A and NR1-1a (D723A)/NR2A trafficked as efficiently as NR1-1a/NR2A, there was a 90% decrease in surface expression for NR1-1a (D732A)/NR2A. (PMID:18990687)
• Data show that expression of NMDA receptor NR1, NR2A, and NR2B subunits is significantly lower in brains of cirrhotic alcoholics than in the corresponding areas in both controls and alcoholics without co-morbid disease. (PMID:18991843)
• A comparison of the molecular bases for NR1/NR2B receptor inhibition versus immobilizing activities of volatile aromatic anesthetics. (PMID:19095845)
• The neuronal coexistence of glutamate and NMDAR1, observed in painful tendinosis but not in controls, suggests a regulatory role in intensified pain signalling. (PMID:19422642)
• This study indicated that statistically significant lower protein and mRNA levels of the N-methyl-D-aspartate receptors, NR-1 and hr-3a in frontal corte in bipolar disorder. (PMID:19488045)
• Nr1 NMDA receptor transgenic mice had reduced auditory potentials in a novel environment compared to wild-type. (PMID:19602553)
• 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)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	grin1b	ENSDARG00000025728
danio_rerio	grin1a	ENSDARG00000027828
mus_musculus	Grin1	ENSMUSG00000026959
rattus_norvegicus	Grin1	ENSRNOG00000011726
drosophila_melanogaster	Nmdar1	FBGN0010399
caenorhabditis_elegans		WBGENE00003774

Paralogs (17): GRIN2D (ENSG00000105464), GRIK5 (ENSG00000105737), GRIN3B (ENSG00000116032), GRIA2 (ENSG00000120251), GRIA3 (ENSG00000125675), GRIK4 (ENSG00000149403), GRID2 (ENSG00000152208), GRIA4 (ENSG00000152578), GRIA1 (ENSG00000155511), GRIN2C (ENSG00000161509), GRIK3 (ENSG00000163873), GRIK2 (ENSG00000164418), GRIK1 (ENSG00000171189), GRID1 (ENSG00000182771), GRIN2A (ENSG00000183454), GRIN3A (ENSG00000198785), GRIN2B (ENSG00000273079)

Protein

Protein identifiers

Glutamate receptor ionotropic, NMDA 1 — Q05586 (reviewed: Q05586)

Alternative names: Glutamate [NMDA] receptor subunit zeta-1, N-methyl-D-aspartate receptor subunit NR1

All UniProt accessions (3): A2AVK2, Q05586, Q5VSF9

UniProt curated annotations — full annotation on UniProt →

Function. Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+). NMDARs participate in synaptic plasticity for learning and memory formation by contributing to the long-term potentiation (LTP). Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+). NMDARs mediate simultaneously the potassium efflux and the influx of calcium and sodium. Each GluN2 or GluN3 subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, Ca2(+) permeability, and binding to allosteric modulators.

Subunit / interactions. Heterotetramer; the NMDAR subunits are modular and harbor tiered domains that function in concert to regulate opening and closing of the cation-selective ion channel pore. Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) (in vitro). Can also form heterotetrameric channels that contain at least two GluN1 subunits and at least two different GluN2 subunits (or a combination of one GluN2 and one GluN3 subunits) (in vitro). In vivo, the subunit composition may vary in function of the expression levels of the different subunits. Found in a complex with GRIN2A or GRIN2B, GRIN3A and PPP2CB. Found in a complex with GRIN2A or GRIN2B and GRIN3B. Interacts with SNX27 (via PDZ domain); the interaction is required for recycling to the plasma membrane when endocytosed and prevent degradation in lysosomes. Interacts with DLG4 and MPDZ. Interacts with LRFN1 and LRFN2. Interacts with MYZAP. Found in a complex with DLG4 and PRR7. Found in a complex with GRIN2B and PRR7. Interacts with PRR7; the interaction is reduced following NMDA receptor activity.

Subcellular location. Cell membrane. Postsynaptic cell membrane. Postsynaptic density membrane. Synaptic cell membrane.

Post-translational modifications. NMDA is probably regulated by C-terminal phosphorylation of an isoform of GRIN1 by PKC. Dephosphorylated on Ser-897 probably by protein phosphatase 2A (PPP2CB). Its phosphorylated state is influenced by the formation of the NMDAR-PPP2CB complex and the NMDAR channel activity.

Disease relevance. Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (NDHMSD) [MIM:614254] An autosomal dominant neurodevelopmental disorder characterized by severe intellectual disability and developmental delay, absent speech, muscular hypotonia, dyskinesia, and hyperkinetic movements. Cortical blindness, cerebral atrophy, and seizures are present in some patients. The disease is caused by variants affecting the gene represented in this entry. Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (NDHMSR) [MIM:617820] An autosomal recessive neurodevelopmental disorder characterized by severe intellectual disability and psychomotor developmental delay, involuntary and stereotypic movements, spasticity, and inability to walk without support. Intractable seizures manifest in some patients. The disease is caused by variants affecting the gene represented in this entry. Developmental and epileptic encephalopathy 101 (DEE101) [MIM:619814] A form of epileptic encephalopathy, a heterogeneous group of early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE101 is an autosomal recessive, severe form characterized by onset of seizures in early infancy. Death in infancy may occur. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. NMDA glutamate receptor activity is inhibited by Mg2(+) in a voltage-dependent manner; Mg2(+)-induced blockade occurs only at negative potentials and decreases with membrane depolarization. 7-chlorokynurenate (50 uM) or Zn2(+) (100 uM) partially inhibit the NMDA glutamate receptor activity, while acide 2-amino-5-phosphonovalerique(100 uM) almost completely blocked the NMDA glutamate receptor activity. Dizocilpine (1 uM) results in long lasting and almost complete block of the NMDA glutamate receptor activity.

Domain organisation. A hydrophobic region that gives rise to the prediction of a transmembrane span does not cross the membrane, but is part of a discontinuously helical region that dips into the membrane and is probably part of the pore and of the selectivity filter. The extracellular N-terminal domain (NTD) is a site of allosteric regulation to modulate overall receptor function. The ligand-binding domain (LBD) binds to glycine (GluN1 and GluN3 subunits) and glutamate (GluN2 subunits) and control opening of the channel gate. The transmembrane domain (TMD) harbors the channel gate and pore.

Similarity. Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR1/GRIN1 subfamily.

Isoforms (7)

UniProt ID	Names	Canonical?
Q05586-1	3, Long, NR1-3	yes
Q05586-2	1, Short, NR1-1
Q05586-3	2, Medium, NR1-2
Q05586-4	4
Q05586-5	5
Q05586-6	6
Q05586-7	7

RefSeq proteins (5): NP_000823, NP_001172019, NP_001172020, NP_015566, NP_067544 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001320	Iontro_rcpt_C	Domain
IPR001508	Iono_Glu_rcpt_met	Family
IPR001828	ANF_lig-bd_rcpt	Domain
IPR015683	Ionotropic_Glu_rcpt	Family
IPR019594	Glu/Gly-bd	Domain
IPR028082	Peripla_BP_I	Homologous_superfamily
IPR049872	NMDA1-like_ligand-bd	Domain
IPR049873	NMDA1-like_N	Domain

Pfam: PF00060, PF01094, PF10613

Catalyzed reactions (Rhea), 3 shown:

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

UniProt features (170 total): strand 40, sequence variant 38, helix 31, glycosylation site 12, turn 9, splice variant 7, topological domain 5, binding site 5, modified residue 4, disulfide bond 4, mutagenesis site 4, transmembrane region 3, region of interest 2, sequence conflict 2, signal peptide 1, chain 1, compositionally biased region 1, intramembrane region 1

Structure

Experimental structures (PDB)

85 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9GJ1	X-RAY DIFFRACTION	1.62
5H8F	X-RAY DIFFRACTION	1.81
9GIC	X-RAY DIFFRACTION	1.82
3BYA	X-RAY DIFFRACTION	1.85
5H8Q	X-RAY DIFFRACTION	1.9
9GIF	X-RAY DIFFRACTION	1.9
2HQW	X-RAY DIFFRACTION	1.9
9GIB	X-RAY DIFFRACTION	1.95
9MUM	X-RAY DIFFRACTION	1.97
9GID	X-RAY DIFFRACTION	2
5KCJ	X-RAY DIFFRACTION	2.09
9GIG	X-RAY DIFFRACTION	2.09
5I2N	X-RAY DIFFRACTION	2.12
5H8H	X-RAY DIFFRACTION	2.23
9GIE	X-RAY DIFFRACTION	2.36
5TP9	X-RAY DIFFRACTION	2.4
9MUL	X-RAY DIFFRACTION	2.4
5KDT	X-RAY DIFFRACTION	2.44
5TPA	X-RAY DIFFRACTION	2.48
5H8N	X-RAY DIFFRACTION	2.5
5I2K	X-RAY DIFFRACTION	2.86
9OOS	ELECTRON MICROSCOPY	3.03
10FD	ELECTRON MICROSCOPY	3.09
9OOT	ELECTRON MICROSCOPY	3.13
9OOR	ELECTRON MICROSCOPY	3.15
9IYQ	ELECTRON MICROSCOPY	3.18
9OOQ	ELECTRON MICROSCOPY	3.2
9IYP	ELECTRON MICROSCOPY	3.27
9D37	ELECTRON MICROSCOPY	3.34
8E96	ELECTRON MICROSCOPY	3.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q05586-F1	82.97	0.55

Antibody-complex structures (SAbDab): 16 — 8E99, 8JIZ, 8JJ0, 8JJ1, 8JJ2, 8VUH, 8VUJ, 8VUL, 8VUN, 8VUQ, 8VUR, 8VUS, 8VUT, 8VUU, 8VUV, 8ZH7

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): 516; 518; 523; 688; 732

Post-translational modifications (4): 889, 890, 896, 897

Disulfide bonds (4): 79–308, 420–454, 436–455, 744–798

Glycosylation sites (12): 61, 203, 239, 276, 300, 350, 368, 440, 471, 491, 674, 771

Mutagenesis-validated functional residues (4):

Position	Phenotype
642	slight decrease in glutamate and glycine agonist potency; mutant channels are activated at 2-fold higher glutamate and g
644	increase in glutamate and glycine agonist potency; mutant channels are activated lower glutamate and glycine concentrati
653	increase in glutamate and glycine agonist potency; mutant channels are activated lower glutamate and glycine concentrati
813	slight decrease in glycine agonist potency; no effect on glutamate agonist potency.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-438066	Unblocking of NMDA receptors, glutamate binding and activation
R-HSA-442982	Ras activation upon Ca2+ influx through NMDA receptor
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6794361	Neurexins and neuroligins
R-HSA-8849932	Synaptic adhesion-like molecules
R-HSA-9609736	Assembly and cell surface presentation of NMDA receptors
R-HSA-9617324	Negative regulation of NMDA receptor-mediated neuronal transmission
R-HSA-9620244	Long-term potentiation

MSigDB gene sets: 560 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, MODULE_274, GOBP_BEHAVIOR, GOMF_GLUTAMATE_GATED_RECEPTOR_ACTIVITY, GOBP_RESPONSE_TO_ACID_CHEMICAL, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS

GO Biological Process (28): monoatomic cation transport (GO:0006812), chemical synaptic transmission (GO:0007268), brain development (GO:0007420), visual learning (GO:0008542), positive regulation of calcium ion transport into cytosol (GO:0010524), propylene metabolic process (GO:0018964), ionotropic glutamate receptor signaling pathway (GO:0035235), sodium ion transmembrane transport (GO:0035725), regulation of membrane potential (GO:0042391), response to ethanol (GO:0045471), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of synaptic plasticity (GO:0048167), regulation of neuronal synaptic plasticity (GO:0048168), protein heterotetramerization (GO:0051290), positive regulation of synaptic transmission, glutamatergic (GO:0051968), calcium ion homeostasis (GO:0055074), excitatory postsynaptic potential (GO:0060079), calcium ion transmembrane transport (GO:0070588), calcium ion transmembrane import into cytosol (GO:0097553), monoatomic cation transmembrane transport (GO:0098655), excitatory chemical synaptic transmission (GO:0098976), positive regulation of reactive oxygen species biosynthetic process (GO:1903428), regulation of monoatomic cation transmembrane transport (GO:1904062), response to glycine (GO:1905429), positive regulation of excitatory postsynaptic potential (GO:2000463), monoatomic ion transport (GO:0006811), calcium-mediated signaling (GO:0019722), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (16): amyloid-beta binding (GO:0001540), NMDA glutamate receptor activity (GO:0004972), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), ligand-gated monoatomic ion channel activity (GO:0015276), ligand-gated sodium channel activity (GO:0015280), glycine binding (GO:0016594), glutamate binding (GO:0016595), glutamate-gated calcium ion channel activity (GO:0022849), signaling receptor activity (GO:0038023), protein-containing complex binding (GO:0044877), glycine-gated cation channel activity (GO:0160212), monoatomic ion channel activity (GO:0005216), calcium channel activity (GO:0005262), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (20): cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), cell surface (GO:0009986), postsynaptic density (GO:0014069), NMDA selective glutamate receptor complex (GO:0017146), dendrite (GO:0030425), neuron projection (GO:0043005), synaptic cleft (GO:0043083), terminal bouton (GO:0043195), dendritic spine (GO:0043197), synapse (GO:0045202), postsynaptic membrane (GO:0045211), excitatory synapse (GO:0060076), synaptic membrane (GO:0097060), postsynaptic density membrane (GO:0098839), neurotransmitter receptor complex (GO:0098878), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Activation of NMDA receptors and postsynaptic events	3
Protein-protein interactions at synapses	2
EPH-Ephrin signaling	1
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1
MAPK1/MAPK3 signaling	1
Post NMDA receptor activation events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
glutamate-gated receptor activity	3
monoatomic cation transmembrane transport	2
monoatomic ion transmembrane transport	2
regulation of biological quality	2
ligand-gated monoatomic cation channel activity	2
amino acid binding	2
carboxylic acid binding	2
cation binding	2
binding	2
presynapse	2
postsynapse	2
synapse	2
monoatomic ion transport	1
anterograde trans-synaptic signaling	1
central nervous system development	1
animal organ development	1
head development	1
visual behavior	1
associative learning	1
positive regulation of cytosolic calcium ion concentration	1
regulation of calcium ion transport into cytosol	1
calcium ion transport into cytosol	1
positive regulation of calcium ion transmembrane transport	1
xenobiotic metabolic process	1
olefin metabolic process	1
glutamate receptor signaling pathway	1
ligand-gated ion channel signaling pathway	1
sodium ion transport	1
response to alcohol	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
modulation of chemical synaptic transmission	1
regulation of synaptic plasticity	1
protein tetramerization	1
protein heterooligomerization	1
synaptic transmission, glutamatergic	1
positive regulation of synaptic transmission	1
regulation of synaptic transmission, glutamatergic	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

19 interactions, top by confidence:

A	B	Type	Score
APP	GRIN1	psi-mi:“MI:0915”(physical association)	0.560
FUS	GRIN1	psi-mi:“MI:0915”(physical association)	0.560
ANKK1	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
GRIN1	Tiam1	psi-mi:“MI:0407”(direct interaction)	0.440
Tiam2	GRIN1	psi-mi:“MI:0407”(direct interaction)	0.440
ERBB4	GRIN1	psi-mi:“MI:0915”(physical association)	0.400
PLCB4	GRIN1	psi-mi:“MI:0915”(physical association)	0.400
CNR2	GRIN1	psi-mi:“MI:2364”(proximity)	0.380
CNR2	GRIN1	psi-mi:“MI:0403”(colocalization)	0.380
GRIN1	BDKRB1	psi-mi:“MI:0915”(physical association)	0.370
GRIN1	PTAFR	psi-mi:“MI:0915”(physical association)	0.370
GPR88	POTEF	psi-mi:“MI:0914”(association)	0.350
GRIN1	GPR89A	psi-mi:“MI:0914”(association)	0.350
BCL11B	MTA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (99): GRIN1 (Affinity Capture-Western), CANX (Affinity Capture-Western), GRIN1 (Affinity Capture-Western), SH3RF1 (Affinity Capture-Western), PARK2 (Affinity Capture-Western), GRIN1 (Affinity Capture-Western), GRIN1 (Affinity Capture-MS), GRIN1 (Synthetic Lethality), GRIN2A (Affinity Capture-Western), DLG4 (Affinity Capture-Western), APLP1 (Affinity Capture-Western), APLP2 (Affinity Capture-Western), GRIN1 (Affinity Capture-Western), APP (Affinity Capture-Western), APP (Reconstituted Complex)

ESM2 similar proteins: A0A1L8F5J9, A0JN27, F1LTR1, F1NBL0, O15294, P35438, P35439, P56558, P61201, P61202, P61203, P61599, P61600, P63138, P79101, P81436, Q03555, Q05586, Q13888, Q15303, Q27HV0, Q2PFM2, Q2TBV5, Q4L208, Q58ED9, Q5R1P0, Q5SP67, Q5ZJ75, Q61527, Q62956, Q6IQT4, Q6IR75, Q6P1K8, Q6P632, Q7ZXR3, Q8BUV3, Q8C6G8, Q8CGY8, Q8R4D1, Q91854

Diamond homologs: A0A1L8F5J9, B3LZ39, B3P2E5, B4GF83, B4I414, B4JHV0, B4KD90, B4LZB5, B4MU83, B4PVB0, B4QWW7, P19491, P23819, P34299, P35438, P35439, P42262, P54952, Q05586, Q10914, Q21415, Q24418, Q296F7, Q38PU7, Q5R1P0, P19490, P19493, P22756, P23818, P39086, P42261, P48058, Q38PU4, Q38PU5, Q38PU8, Q5R4M0, Q60934, Q9Z2W8, Q91756, Q16478

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
GRIN1	“form complex”	“NMDA receptor_2A”	binding
GRIN1	“form complex”	“NMDA receptor_2B”	binding
GRIN1	“form complex”	“NMDA receptor_2C”	binding
GRIN1	“form complex”	“NMDA receptor_2D”	binding
GRIN2C	“up-regulates activity”	GRIN1	binding
PRKCG	“up-regulates activity”	GRIN1	phosphorylation
PRKCA	“up-regulates activity”	GRIN1	phosphorylation
LNX1	“down-regulates quantity by destabilization”	GRIN1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

1267 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	54
Uncertain significance	403
Likely benign	588
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1208495	NM_007327.4(GRIN1):c.1658C>T (p.Ser553Leu)	Pathogenic
1329920	NM_007327.4(GRIN1):c.1950C>A (p.Asn650Lys)	Pathogenic
1445348	NM_007327.4(GRIN1):c.2438T>C (p.Met813Thr)	Pathogenic
1452432	NM_007327.4(GRIN1):c.2443G>C (p.Gly815Arg)	Pathogenic
1483551	NM_007327.4(GRIN1):c.1324_1325dup (p.Ser443fs)	Pathogenic
1484756	NM_007327.4(GRIN1):c.529C>T (p.Gln177Ter)	Pathogenic
1525992	NM_007327.4(GRIN1):c.394-1G>C	Pathogenic
1683956	NM_007327.4(GRIN1):c.1852G>A (p.Gly618Ser)	Pathogenic
1685863	NM_007327.4(GRIN1):c.1668G>T (p.Gln556His)	Pathogenic
1685864	NM_007327.4(GRIN1):c.1832G>T (p.Trp611Leu)	Pathogenic
1700197	NM_007327.4(GRIN1):c.1921A>T (p.Met641Leu)	Pathogenic
1713267	NM_007327.4(GRIN1):c.1665G>T (p.Met555Ile)	Pathogenic
1922738	NM_007327.4(GRIN1):c.1069C>T (p.Gln357Ter)	Pathogenic
1949360	NM_007327.4(GRIN1):c.1078A>T (p.Lys360Ter)	Pathogenic
2000563	NM_007327.4(GRIN1):c.2030_2034del (p.Asp677fs)	Pathogenic
208743	NM_007327.4(GRIN1):c.2443G>A (p.Gly815Arg)	Pathogenic
2097493	NM_007327.4(GRIN1):c.1798_1805del (p.Ala600fs)	Pathogenic
2119508	NM_007327.4(GRIN1):c.118C>T (p.Gln40Ter)	Pathogenic
235846	NM_007327.4(GRIN1):c.1670C>G (p.Pro557Arg)	Pathogenic
2499551	NM_007327.4(GRIN1):c.2451C>A (p.Phe817Leu)	Pathogenic
2836372	NM_007327.4(GRIN1):c.1736del (p.Leu579fs)	Pathogenic
2866137	NM_007327.4(GRIN1):c.1214A>T (p.Gln405Leu)	Pathogenic
2910238	NM_007327.4(GRIN1):c.2365G>A (p.Asp789Asn)	Pathogenic
29725	NM_007327.4(GRIN1):c.1984G>A (p.Glu662Lys)	Pathogenic
29726	NM_007327.4(GRIN1):c.1679_1681dup (p.Ser560dup)	Pathogenic
3024338	NM_007327.4(GRIN1):c.1904T>G (p.Val635Gly)	Pathogenic
3340376	NM_007327.4(GRIN1):c.1921A>C (p.Met641Leu)	Pathogenic
3544383	NM_007327.4(GRIN1):c.2209G>A (p.Glu737Lys)	Pathogenic
3649450	NM_007327.4(GRIN1):c.733dup (p.Tyr245fs)	Pathogenic
3897183	NM_007327.4(GRIN1):c.1676A>G (p.Gln559Arg)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

6189 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:137139574:G:C	G30R	1.000
9:137139575:G:A	G30D	1.000
9:137139577:G:C	A31P	1.000
9:137139578:C:A	A31E	1.000
9:137139584:T:C	L33P	1.000
9:137139611:T:C	F42S	1.000
9:137139701:T:A	I72N	1.000
9:137139710:C:A	A75D	1.000
9:137139713:T:C	L76P	1.000
9:137139721:T:A	C79S	1.000
9:137139721:T:C	C79R	1.000
9:137139722:G:A	C79Y	1.000
9:137139722:G:C	C79S	1.000
9:137139722:G:T	C79F	1.000
9:137139723:C:G	C79W	1.000
9:137139731:T:C	L82P	1.000
9:137142019:G:C	A89P	1.000
9:137142020:C:A	A89D	1.000
9:137142023:T:A	I90N	1.000
9:137142026:T:C	L91P	1.000
9:137142074:T:A	V107D	1.000
9:137142077:C:A	S108Y	1.000
9:137142077:C:T	S108F	1.000
9:137142085:G:C	A111P	1.000
9:137142086:C:A	A111D	1.000
9:137142088:G:C	G112R	1.000
9:137142089:G:A	G112D	1.000
9:137142091:T:C	F113L	1.000
9:137142092:T:C	F113S	1.000
9:137142092:T:G	F113C	1.000

dbSNP variants (sampled 300 via entrez): RS1000169516 (9:137153250 C>A), RS1000173957 (9:137138920 A>C), RS1000266736 (9:137147249 CCA>C), RS1000287774 (9:137165699 G>A), RS1000296544 (9:137159055 G>C,T), RS1000297337 (9:137142430 G>A), RS1000398444 (9:137144345 C>A,T), RS1000433736 (9:137159268 C>A,T), RS1000520534 (9:137155284 C>T), RS1000578166 (9:137148886 G>A,T), RS1000629215 (9:137157744 G>A), RS1000676809 (9:137160682 G>A), RS1000786690 (9:137151552 C>G), RS1000903352 (9:137151722 G>C), RS1000976103 (9:137155116 T>C)

Disease associations

OMIM: gene MIM:138249 | disease phenotypes: MIM:614254, MIM:617820, MIM:209850, MIM:619814, MIM:117100, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant	Definitive	Autosomal dominant
neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive	Definitive	Autosomal recessive
complex neurodevelopmental disorder	Definitive	Autosomal dominant
developmental and epileptic encephalopathy 101	Strong	Autosomal recessive
GRIN1-related complex neurodevelopmental disorder	Strong	Autosomal recessive
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AR
complex neurodevelopmental disorder	Definitive	AD

Mondo (14): neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (MONDO:0013655), neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (MONDO:0060629), autism (MONDO:0005260), developmental and epileptic encephalopathy 101 (MONDO:0030727), prostate cancer (MONDO:0008315), intellectual disability (MONDO:0001071), autism spectrum disorder (MONDO:0005258), self-limited epilepsy with centrotemporal spikes (MONDO:0007295), neurodevelopmental disorder (MONDO:0700092), hemimegalencephaly (MONDO:0020492), developmental and epileptic encephalopathy, 1 (MONDO:0010632), complex neurodevelopmental disorder (MONDO:0100038), autosomal dominant non-syndromic intellectual disability (MONDO:0015802), GRIN1-related complex neurodevelopmental disorder (MONDO:1060123)

Orphanet (5): Familial prostate cancer (Orphanet:1331), Self-limited epilepsy with centrotemporal spikes (Orphanet:1945), Hemimegalencephaly (Orphanet:99802), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000717	Autism

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002037_2	Post-traumatic stress disorder (asjusted for relatedness)	5.000000e-06

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D065705	Hemimegalencephaly	C05.660.207.536.500; C10.500.507.400.249.500; C16.131.621.207.532.500; C16.131.666.507.400.249.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (8): CHEMBL1907603 (PROTEIN COMPLEX), CHEMBL1907604 (PROTEIN COMPLEX), CHEMBL2015 (SINGLE PROTEIN), CHEMBL2094124 (PROTEIN COMPLEX GROUP), CHEMBL3038504 (PROTEIN COMPLEX), CHEMBL3038505 (PROTEIN COMPLEX), CHEMBL5483086 (PROTEIN COMPLEX), CHEMBL6066548 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

39 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,434,583 (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
CHEMBL52440	DEXTROMETHORPHAN	4	33,223
CHEMBL742	KETAMINE	4	101,983
CHEMBL771	CYCLOSERINE	4	23,487
CHEMBL807	MEMANTINE	4	34,597
CHEMBL95	TACRINE	4	35,360
CHEMBL1699	MEMANTINE HYDROCHLORIDE	4	8,827
CHEMBL395091	ESKETAMINE	4	958
CHEMBL55	PENTAMIDINE	4	27,049
CHEMBL660	AMANTADINE	4	69,750
CHEMBL592	LEVORPHANOL	4	75,131
CHEMBL71	CHLORPROMAZINE	4	45,827
CHEMBL86715	PROCYCLIDINE	4	5,456
CHEMBL900	ORPHENADRINE	4	8,087
CHEMBL350719	ESMETHADONE	3	26,004
CHEMBL5095095	DALZANEMDOR	3	20
CHEMBL589390	LATREPIRDINE	3	466
CHEMBL575060	GLUTAMIC ACID	3	929,756
CHEMBL1254766	DEXTRORPHAN	2	6,521
CHEMBL159659	LEVOMETHADONE	2	1,664
CHEMBL159660	ALPHAMETHADOL	2	417
CHEMBL17350	TRAXOPRODIL	2
CHEMBL182066	RADIPRODIL	2
CHEMBL275528	PHENCYCLIDINE	2
CHEMBL284237	DIZOCILPINE	2
CHEMBL28564	ELIPRODIL	2
CHEMBL305187	IFENPRODIL	2
CHEMBL5095074	ONFASPRODIL	2
CHEMBL1165411	DEXOXADROL	2
CHEMBL162243	BETAMETHADOL	2
CHEMBL2106325	DIMEMORFAN	2

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1126442	Toxicity	3	methamphetamine	Psychotic Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1126442	GRIN1	3	2.25	1	methamphetamine
rs11146020	GRIN1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — Ionotropic glutamate receptors

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
compound 8 [PMID: 17562362}	Antagonist	9.0	pIC50
L701324	Antagonist	8.7	pIC50
[3H]MDL105519	Antagonist	8.52	pKd
GV196771A	Antagonist	8.4	pKi
L689560	Antagonist	8.13	pIC50

Binding affinities (BindingDB)

187 measured of 192 human assays (192 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-[2-[(3aR,6aS)-5-(4-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	4.41 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aS,6aR)-5-(2-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]phenol	IC50	4.44 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[(1R)-2-[(3aS,6aR)-5-phenoxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	5.24 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[(1S)-2-[(3aR,6aS)-5-phenoxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	5.25 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aS,6aR)-5-phenoxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	5.72 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aR,6aS)-5-phenoxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]phenol	IC50	5.96 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aR,6aS)-5-(2-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	6.2 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aS,6aR)-5-(2,4-difluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	6.81 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[(1S)-2-[(3aR,6aS)-5-(2-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	8.3 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[(1R)-2-[(3aR,6aS)-5-(2-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	8.5 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aR,6aS)-5-(2,4-difluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]phenol	IC50	8.62 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aR,6aS)-5-(2,3-difluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	8.78 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aS,6aR)-5-phenylsulfanyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]phenol	IC50	9.36 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aR,6aS)-5-(2,6-difluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	9.6 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
2-[(3aR,6aS)-5-phenoxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethanone	IC50	10.7 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aR,6aS)-5-(4-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]phenol	IC50	13 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aR,6aS)-5-(3,4-difluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]phenol	IC50	14 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aR,6aS)-5-(2-fluoro-4-methylphenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	14.4 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
2-[(3aS,6aR)-5-(2-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethanone	IC50	16.8 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aS,6aR)-5-(3,4-difluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	17.8 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aR,6aS)-5-(4-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]phenol	IC50	17.8 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[[(3aR,6aS)-2-[2-hydroxy-2-(5-hydroxy-2-pyridinyl)ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]oxy]benzonitrile	IC50	18 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aR,6aS)-5-(4-fluorophenyl)sulfanyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]phenol	IC50	19.2 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[(1S)-2-[(3aS,6aR)-5-[(2-fluoro-3-pyridinyl)oxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	20 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aR,6aS)-5-(2-fluorophenyl)sulfanyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	20.6 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aR,6aS)-5-[(2-fluoro-3-pyridinyl)oxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	20.9 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
cis-(1R,2R)-2-[2-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-7-fluoro-4-oxopyrido[1,2-a]pyrimidin-6-yl]cyclopropane-1-carbonitrile	EC50	21 nM	US-10280165: Pyridopyrimidinones and methods of use thereof
4-[2-[(3aS,6aR)-5-[(2-fluoro-3-pyridinyl)oxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]-2-fluorophenol	IC50	21.7 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aR,6aS)-5-(2-fluoro-3-methylphenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	23.4 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
(1R,2R)-2-[2-[[5-chloro-3- (trifluoromethyl)pyrazol-1- yl]methyl]-4-oxo-pyrido[1,2- a]pyrimidin-6- yl]cyclopropanecarbonitrile	EC50	24 nM	US-10280165: Pyridopyrimidinones and methods of use thereof
4-[2-[(3aR,6aS)-5-(2,6-difluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]phenol	IC50	26.3 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
2-[(3aS,6aR)-5-phenylsulfanyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethanone	IC50	26.7 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
2-[(3aS,6aR)-5-(2,6-difluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethanone	IC50	29.3 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aR,6aS)-5-(4-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]-2-fluoropyridin-3-ol	IC50	30.2 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aS,6aR)-5-(4-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]-2-fluorophenol	IC50	30.5 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
cis-(1R,2R)-2-[7-chloro-2-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-4-oxopyrido[1,2-a]pyrimidin-6-yl]cyclopropane-1-carbonitrile	EC50	36.8 nM	US-10280165: Pyridopyrimidinones and methods of use thereof
6-[2-[(3aS,6aR)-5-(3,4-difluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	37.6 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aS,6aR)-5-(2-chlorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	38 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
cis-(1R,2R)-2-[2-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-8-methyl-4-oxopyrido[1,2-a]pyrimidin-6-yl]cyclopropane-1-carbonitrile	EC50	39 nM	US-10280165: Pyridopyrimidinones and methods of use thereof
2-[(3aR,6aS)-5-(2,4-difluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethanone	IC50	41.1 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aS,6aR)-5-(4-methoxyphenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]-2-fluorophenol	IC50	41.5 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
2-[(3aR,6aS)-5-(4-methoxyphenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethanone	IC50	46.4 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
2-[(3aR,6aS)-5-(4-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethanone	IC50	47 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[[(3aR,6aS)-2-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]oxy]benzonitrile	IC50	47.4 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
6-[2-[(3aS,6aR)-5-(2-fluoro-3-methoxyphenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]pyridin-3-ol	IC50	50.8 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aR,6aS)-5-(4-methoxyphenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]phenol	IC50	51.6 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
4-[2-[(3aS,6aR)-5-pyridin-3-yloxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl]-2-fluorophenol	IC50	52.1 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
2-[(3aR,6aS)-5-(4-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-(3-fluoro-4-hydroxyphenyl)ethanone	IC50	53.2 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
2-[(3aR,6aS)-5-(4-fluorophenoxy)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethanone	IC50	53.4 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
2-[(3aR,6aS)-5-[(6-fluoro-3-pyridinyl)oxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethanone	IC50	55.2 nM	US-10239835: N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B

ChEMBL bioactivities

3010 potent at pChembl≥5 of 3342 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	IC50	0.2	nM	CHEMBL12513
9.40	Ki	0.4	nM	CHEMBL416690
9.30	Ki	0.5	nM	CHEMBL423244
9.30	IC50	0.5	nM	CHEMBL276708
9.22	Ki	0.6	nM	CHEMBL159675
9.18	Ki	0.66	nM	CHEMBL6173708
9.17	Ki	0.68	nM	CHEMBL65693
9.15	Ki	0.7	nM	CHEMBL158737
9.15	IC50	0.7	nM	CHEMBL274422
9.14	IC50	0.72	nM	CHEMBL65693
9.10	Ki	0.8	nM	CHEMBL159762
9.10	IC50	0.8	nM	CHEMBL12513
9.09	Ki	0.82	nM	CHEMBL65454
9.07	Ki	0.85	nM	CHEMBL68134
9.02	IC50	0.95	nM	MEMANTINE
9.02	Ki	0.96	nM	CHEMBL39881
9.00	Ki	1	nM	CHEMBL159761
9.00	IC50	1	nM	CHEMBL248247
9.00	IC50	1	nM	CHEMBL5916023
9.00	IC50	1	nM	CHEMBL5924093
9.00	IC50	1	nM	CHEMBL5958626
9.00	IC50	1	nM	CHEMBL5963003
9.00	IC50	1	nM	CHEMBL5824795
9.00	IC50	1	nM	CHEMBL5795644
9.00	IC50	1	nM	CHEMBL5820376
9.00	IC50	1	nM	CHEMBL5994695
9.00	IC50	1	nM	CHEMBL5499329
9.00	IC50	1	nM	CHEMBL6056265
9.00	IC50	1	nM	CHEMBL5992919
9.00	IC50	1	nM	CHEMBL5929772
9.00	IC50	1	nM	CHEMBL5904651
9.00	IC50	1	nM	CHEMBL12804
9.00	Ki	0.99	nM	CHEMBL436521
8.96	IC50	1.1	nM	CHEMBL274422
8.96	Ki	1.1	nM	CHEMBL64941
8.92	IC50	1.2	nM	CHEMBL12242
8.92	Ki	1.2	nM	DIZOCILPINE
8.89	Ki	1.3	nM	CHEMBL159416
8.85	Ki	1.4	nM	CHEMBL159902
8.85	Ki	1.4	nM	CHEMBL159453
8.85	Ki	1.4	nM	CHEMBL5185347
8.85	IC50	1.4	nM	CHEMBL436521
8.82	Ki	1.5	nM	CHEMBL6160888
8.82	Ki	1.5	nM	CHEMBL65231
8.82	IC50	1.5	nM	CHEMBL537478
8.82	IC50	1.5	nM	CHEMBL274422
8.82	IC50	1.5	nM	CHEMBL273662
8.80	Ki	1.6	nM	CHEMBL159790
8.77	Ki	1.7	nM	CHEMBL160027
8.77	IC50	1.7	nM	CHEMBL269683

PubChem BioAssay actives

1091 with measured affinity, of 2729 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
[7-(4-chlorophenyl)-2,3-dioxo-1,4-dihydroquinoxalin-5-yl]methylphosphonic acid	144677: Inhibitory activity against Xenopus laevis oocyte expressing 1A/2A heteromeric human NMDA (hNMDA) receptor	ic50	0.0002	uM
2-[[4-[(4-methylphenyl)methyl]piperidin-1-yl]methyl]-3H-benzimidazol-5-ol	146213: Compound was evaluated for in vitro inhibition of [3H][(E)-N-(2-methoxybenzyl)cinnamamidine binding to human NR1a/NR2B receptors expressed in LtK-cells	ki	0.0004	uM
(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylphosphonic acid	144039: Compound was tested in vitro for its inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor by using [3H]CGP-39653 binding assay	ic50	0.0005	uM
(E)-N’-[(2-ethoxyphenyl)methyl]-3-phenylprop-2-enimidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0005	uM
(E)-3-phenyl-N’-[[2-(trifluoromethoxy)phenyl]methyl]prop-2-enimidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0006	uM
[(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)-hydroxymethyl]phosphonic acid	144694: Inhibitory activity against Xenopus laevis oocyte expressing 1A/2B heteromeric human NMDA (hNMDA) receptor	ic50	0.0007	uM
N-[2-[(4-phenoxyphenyl)methyl]-3H-benzimidazol-5-yl]methanesulfonamide	102503: In vitro inhibition of Glu/Gly stimulated [Ca2+] influx in LtK-cells expressing the hNR1a/NR2B receptor	ic50	0.0007	uM
(E)-N’-[(2-methoxyphenyl)methyl]-3-phenylprop-2-enimidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0007	uM
2-[[4-[(2,6-difluorophenyl)methyl]piperidin-1-yl]methyl]-3H-benzimidazol-5-ol	146213: Compound was evaluated for in vitro inhibition of [3H][(E)-N-(2-methoxybenzyl)cinnamamidine binding to human NR1a/NR2B receptors expressed in LtK-cells	ki	0.0008	uM
2-[[4-[(2-fluorophenyl)methyl]piperidin-1-yl]methyl]-3H-benzimidazol-5-ol	146213: Compound was evaluated for in vitro inhibition of [3H][(E)-N-(2-methoxybenzyl)cinnamamidine binding to human NR1a/NR2B receptors expressed in LtK-cells	ki	0.0008	uM
(E)-N’-[(3-chlorophenyl)methyl]-3-phenylprop-2-enimidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0008	uM
Memantine	755470: Antagonist activity at recombinant GluN1/GluN2A receptor (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of glycine/glutamate-induced inward current at -70mV by two-electrode voltage clamp assay	ic50	0.0009	uM
(7-fluoro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylphosphonic acid	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0010	uM
N-[2-[(4-benzylpiperidin-1-yl)methyl]-3H-benzimidazol-5-yl]methanesulfonamide	146213: Compound was evaluated for in vitro inhibition of [3H][(E)-N-(2-methoxybenzyl)cinnamamidine binding to human NR1a/NR2B receptors expressed in LtK-cells	ki	0.0010	uM
2-[(12S)-7-bromo-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]-N-phenylacetamide	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0010	uM
2-[(6-chloro-7-methyl-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)-methylsulfonylamino]acetic acid	308473: Antagonist activity at human NMDA NR1 receptor	ic50	0.0010	uM
(E)-N’-[(2-chlorophenyl)methyl]-3-phenylprop-2-enimidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0010	uM
2-[[4-[(4-fluorophenyl)methyl]piperidin-1-yl]methyl]-3H-benzimidazol-5-ol	146213: Compound was evaluated for in vitro inhibition of [3H][(E)-N-(2-methoxybenzyl)cinnamamidine binding to human NR1a/NR2B receptors expressed in LtK-cells	ki	0.0011	uM
(1S,9R)-1-methyl-16-azatetracyclo[7.6.1.02,7.010,15]hexadeca-2,4,6,10,12,14-hexaene	156805: The compound was tested for its ability to block PCP N-methyl-D-aspartate glutamate receptor at the PCP (phencyclidine) binding site in postmortem human frontal cortex.	ki	0.0012	uM
[hydroxy-(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]phosphonic acid	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0012	uM
N’-[(2-methoxyphenyl)methyl]naphthalene-2-carboximidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0013	uM
2-[(11S)-7-bromo-11-ethyl-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]acetic acid	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0014	uM
(E)-N’-[(3,5-dichlorophenyl)methyl]-3-phenylprop-2-enimidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0014	uM
(E)-3-phenyl-N’-[[2-(trifluoromethyl)phenyl]methyl]prop-2-enimidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0014	uM
(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylphosphonic acid	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0015	uM
[(benzylamino)-(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]phosphonic acid;hydrobromide	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0015	uM
2-[(4-benzylpiperidin-1-yl)methyl]-3H-benzimidazol-5-ol	146213: Compound was evaluated for in vitro inhibition of [3H][(E)-N-(2-methoxybenzyl)cinnamamidine binding to human NR1a/NR2B receptors expressed in LtK-cells	ki	0.0015	uM
N’-[(3-chlorophenyl)methyl]naphthalene-2-carboximidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0016	uM
(7-chloro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylphosphonic acid	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0017	uM
(E)-N’-benzyl-3-(3,4-difluorophenyl)prop-2-enimidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0017	uM
2-[[1-[4-chloro-3-(difluoromethoxy)phenyl]triazol-4-yl]methoxy]-5-methylpyrimidine	1967556: Negative allosteric modulation of human GluN1A/GluN2B receptor expressed in T-REX-CHO cells preincubated for 5 mins followed by glutamate and glycine addition and measured after 5 mins by FLIPR assay	ic50	0.0019	uM
2-(2-chloro-5-methylsulfanylphenyl)-1-methyl-1-(3-methylsulfanylphenyl)guanidine	143453: In vitro displacement of [3H]MK-801 from N-methyl-D-aspartate glutamate receptor	ki	0.0019	uM
(E)-N’-[(3-methoxyphenyl)methyl]-3-phenylprop-2-enimidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0019	uM
2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]-2-oxo-N-(2-oxo-1,3-dihydrobenzimidazol-5-yl)acetamide	242374: Inhibition of NMDA-evoked increased intracellular [Ca2+] in cells expressing NR1/NR2B receptor	ic50	0.0020	uM
2-[2-deuterio-6-(4-fluoro-3-methylphenyl)pyrrolo[3,2-b]pyridin-1-yl]-N,N-dimethylacetamide	1379888: Modulation of recombinant human GluN1/GluN2B NMDA receptor expressed in mammalian cells assessed as inhibition of glutamate/glycine-induced intracellular calcium flux pretreated for 5 mins followed by glutamate/glycine addition measured after 5 mins by calcium 5 dye based FLIPR assay	ic50	0.0020	uM
1-[4-(4-cyclohexylpiperazin-1-yl)butyl]-3,4-dihydroquinolin-2-one	1511006: Displacement of [3H]ifenprodil from GluN1a/GluN2B (unknown origin) expressed in mouse L(tk-) cell membranes after 120 mins by solid scintillation counting method	ki	0.0020	uM
2-[(6,7-dichloro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)-methylsulfonylamino]acetic acid	308473: Antagonist activity at human NMDA NR1 receptor	ic50	0.0020	uM
[(benzylamino)-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]phosphonic acid;hydrobromide	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0020	uM
2-[(7-chloro-6-methyl-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)-methylsulfonylamino]acetic acid	308473: Antagonist activity at human NMDA NR1 receptor	ic50	0.0020	uM
2-[[2-(3,4-dihydro-1H-isoquinolin-2-yl)-4-pyridinyl]amino]ethanol	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0020	uM
N-[2-[(4-phenoxyphenyl)methyl]-3H-benzimidazol-5-yl]ethanesulfonamide	102503: In vitro inhibition of Glu/Gly stimulated [Ca2+] influx in LtK-cells expressing the hNR1a/NR2B receptor	ic50	0.0021	uM
2-[(12S)-7-bromo-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]acetic acid	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0023	uM
2-(7-bromo-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl)-N-phenylacetamide	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0026	uM
6,7-dichloro-5-[1-(1,2,4-triazol-4-yl)propyl]-1,4-dihydroquinoxaline-2,3-dione	1859120: Displacement of [3H]L-689560 from NMDA receptor (unknown origin)	ic50	0.0026	uM
(E)-N’-[(2,5-dichlorophenyl)methyl]-3-phenylprop-2-enimidamide	144050: Displacement of [3H]ifenprodil binding to recombinant human NR1a/NR2B receptors expressed in L(tk-) cells	ki	0.0027	uM
2-(4-benzylpiperidin-1-yl)-2-oxo-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide	242374: Inhibition of NMDA-evoked increased intracellular [Ca2+] in cells expressing NR1/NR2B receptor	ic50	0.0030	uM
2-[(11S)-7-bromo-11-methyl-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]-N-phenylacetamide	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0030	uM
[(cyclohexylmethylamino)-(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]phosphonic acid;hydrochloride	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0030	uM
2-(3,4-dihydro-1H-isoquinolin-2-yl)pyridin-4-amine	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0030	uM
2-(3,4-dihydro-1H-isoquinolin-2-yl)-6-ethylpyridin-4-amine	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0030	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
ochratoxin A	increases acetylation, increases expression, decreases expression	2
Glyphosate	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Lead	affects expression, affects methylation	2
Smoke	decreases expression, increases abundance, increases expression	2
Tretinoin	decreases reaction, increases expression, affects expression, affects binding, affects localization	2
Dizocilpine Maleate	increases response to substance, decreases activity, affects cotreatment, decreases reaction	2
Aflatoxin B1	decreases expression, decreases methylation	2
Excitatory Amino Acid Agonists	increases activity, affects cotreatment, decreases reaction, increases response to substance, affects binding	2
Particulate Matter	increases expression, affects methylation	2
aristolochic acid I	decreases expression	1
bisphenol A	decreases expression	1
carbamylhydrazine	decreases activity	1
arsenite	increases methylation	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
cypermethrin	decreases expression	1
fenvalerate	decreases expression	1
sodium arsenite	increases expression	1
aflatoxin B2	decreases methylation	1
beta-methylcholine	affects expression	1
fumonisin B1	decreases expression	1
notoginsenoside R1	affects cotreatment, increases response to substance	1
SN50 peptide	affects localization, decreases reaction, increases expression, affects binding	1
bisphenol S	decreases expression	1
bisphenol AF	decreases expression	1
Gabapentin	decreases expression	1
Cyclic AMP	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases expression	1
Ascorbic Acid	affects cotreatment, increases expression	1

ChEMBL screening assays

481 unique, capped per target: 435 binding, 40 functional, 5 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1015706	Functional	Antagonist activity at NR1/2B receptor expressed in xenopus laevis at pH 6.9 by two electrode voltage clamp method	Theoretical studies on the structure and symmetry of the transmembrane region of glutamatergic GluR5 receptor. — J Med Chem
CHEMBL1036606	Binding	Inhibition of human NR1/NR2B receptor	Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists. — J Med Chem
CHEMBL3871166	ADMET	Positive allosteric modulation of GluN1/GluN2B receptor (unknown origin) expressed in HEK293 cells assessed as increase in glutamate-induced calcium flux at 125 uM measured at time interval of 5 mins in presence of saturating glycine by cal	GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved in Vivo Profile. — ACS Med Chem Lett

Cellosaurus cell lines

9 cell lines: 4 transformed cell line, 3 spontaneously immortalized cell line, 1 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3TY	CHO-hGluN1-hGluN2A	Spontaneously immortalized cell line	Female
CVCL_B3TZ	CHO-hGluN1-hGluN2B	Spontaneously immortalized cell line	Female
CVCL_B3U0	CHO-hGluN1-hGluN2C	Spontaneously immortalized cell line	Female
CVCL_C9D2	B’SYS HEK 293 NMDA NR1/NR2A	Transformed cell line	Female
CVCL_C9D3	B’SYS HEK 293 NMDA NR1/NR2B	Transformed cell line	Female
CVCL_C9D4	B’SYS HEK 293 NMDA NR1/NR2D	Transformed cell line	Female
CVCL_C9E4	SB Drug Discovery Inducible HEK-GluN1/2A	Transformed cell line	Female
CVCL_D0F4	GWCMCi006-A	Induced pluripotent stem cell	Male
CVCL_D8M2	Ubigene HCT 116 GRIN1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms