GABRB2

Summary

GABRB2 (gamma-aminobutyric acid type A receptor subunit beta2, HGNC:4082) is a protein-coding gene on chromosome 5q34, encoding Gamma-aminobutyric acid receptor subunit beta-2 (P47870). Beta subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.

The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 2 subunit. It is mapped to chromosome 5q34 in a cluster comprised of genes encoding alpha 1 and gamma 2 subunits of the GABA A receptor. Alternative splicing of this gene generates 2 transcript variants, differing by a 114 bp insertion.

Source: NCBI Gene 2561 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 634 total — 17 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 58
• Druggable target: yes — 47 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001371727

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4082
Approved symbol	GABRB2
Name	gamma-aminobutyric acid type A receptor subunit beta2
Location	5q34
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000145864
Ensembl biotype	protein_coding
OMIM	600232
Entrez	2561

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 11 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000274547, ENST00000353437, ENST00000393959, ENST00000517547, ENST00000517901, ENST00000520240, ENST00000522758, ENST00000523730, ENST00000612710, ENST00000674514, ENST00000674988, ENST00000675081, ENST00000675245, ENST00000675303, ENST00000675381, ENST00000675682, ENST00000675746, ENST00000675773, ENST00000965237

RefSeq mRNA: 3 — MANE Select: NM_001371727 NM_000813, NM_001371727, NM_021911

CCDS: CCDS4354, CCDS4355

Canonical transcript exons

ENST00000393959 — 10 exons

Exon	Start	End
ENSE00001021240	161334752	161334904
ENSE00001021241	161330883	161331127
ENSE00001085891	161326368	161326481
ENSE00001085898	161336632	161336769
ENSE00001517004	161546567	161546725
ENSE00001712165	161459624	161459844
ENSE00003548654	161546322	161546413
ENSE00003642061	161545227	161545294
ENSE00003675528	161410975	161411057
ENSE00003897126	161288436	161294428

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 99.82.

FANTOM5 (CAGE): breadth broad, TPM avg 5.0297 / max 574.1446, expressed in 262 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64669	3.0478	172
64668	0.8147	92
64678	0.2621	90
64676	0.2463	72
64672	0.1560	54
64670	0.1306	57
64673	0.0949	50
64677	0.0901	40
64671	0.0770	43
64666	0.0390	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.82	gold quality
endothelial cell	CL:0000115	99.56	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.32	gold quality
postcentral gyrus	UBERON:0002581	99.18	gold quality
parietal lobe	UBERON:0001872	99.07	gold quality
middle temporal gyrus	UBERON:0002771	98.39	gold quality
entorhinal cortex	UBERON:0002728	98.34	gold quality
buccal mucosa cell	CL:0002336	97.99	gold quality
lateral globus pallidus	UBERON:0002476	97.71	gold quality
superior frontal gyrus	UBERON:0002661	97.67	gold quality
primary visual cortex	UBERON:0002436	96.52	gold quality
occipital lobe	UBERON:0002021	95.66	gold quality
pons	UBERON:0000988	94.17	gold quality
cerebellar cortex	UBERON:0002129	92.73	gold quality
cerebellar hemisphere	UBERON:0002245	92.65	gold quality
substantia nigra pars compacta	UBERON:0001965	92.23	gold quality
cerebellum	UBERON:0002037	92.19	gold quality
prefrontal cortex	UBERON:0000451	91.95	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.71	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.85	gold quality
frontal cortex	UBERON:0001870	90.62	gold quality
cerebellar vermis	UBERON:0004720	90.27	gold quality
neocortex	UBERON:0001950	89.69	gold quality
cerebral cortex	UBERON:0000956	89.47	gold quality
ventral tegmental area	UBERON:0002691	89.19	gold quality
substantia nigra pars reticulata	UBERON:0001966	88.53	gold quality
right frontal lobe	UBERON:0002810	87.68	gold quality
temporal lobe	UBERON:0001871	86.90	gold quality
telencephalon	UBERON:0001893	86.69	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	82.00
E-HCAD-25	yes	47.59
E-ANND-3	yes	6.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

363 targeting GABRB2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-8068	99.98	73.85	2376

Literature-anchored findings (GeneRIF, showing 40)

• This report indicates pronounced adaptive changes in the expression of these GABA(A) receptor subunits related to seizure activity and indicates altered assembly of GABA(A) receptors in temporal lobe epilepsy. (PMID:14503638)
• Properties of recombinant GABRAB2 receptor vary significantly from one expression system to another most likely due to differences in endogenous modulators. (PMID:14625018)
• Single nucleotide polymorphisms are associated with schizophrenia. (PMID:14699426)
• Two etomidate sites allosterically enhance GABA(A) receptor subunit gating independently of agonist binding. (PMID:15016806)
• extracellular domain models show subunit arrangement of GABA-A receptors (PMID:15033447)
• No significant difference in mRNA expression is found between the control and alcoholic case groups in either the superior frontal or motor cortex for the GABA A beta 2 isoform (PMID:15337300)
• Six Single Nucleotide Polymorphisms in GABRB2 were genotyped for a case-control association study with the cycloid psychosis subtype of Schizophrenia in the German population using two methods for SNP genotyping. (PMID:16472798)
• a conserved lysine in the TM2-3 of alpha1, beta2, and gamma2 of the GABA-A receptor has an asymmetric function in different GABAA subunits (PMID:16627470)
• Cross-population validation of GABRB2 association with schizophrenia has been obtained with JP and GE subjects, with the genotype-disease correlations being strongest in systematic schizophrenia, the most severe subtype of the disease. (PMID:16950232)
• Results do not support the hypothesis that genetic variation at the GABRB2 locus plays a major role in schizophrenic patients of european descent. (PMID:17167345)
• A cation-pi interaction between GABA and a tyrosine on loop A has been identified by unnatural amino acid mutagenesis, the first example of a cation-pi interaction with a loop A residue in a cysteine-loop neurotransmitter receptor. (PMID:17251430)
• study suggests that the GABRB2 and GAD1 genes individually, as well as the combined effects of the polymorphism in the GAD1, GAD2 and GABRB2 genes, are associated with schizophrenia in the Chinese population (PMID:17412563)
• Electrophysiological analysis showed that this long beta(2) isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABA(A) receptor function by energy depletion (PMID:17520021)
• built homology models of the ion pores of alpha1beta2 and alpha1beta2gamma2 GABA(A)-R using coordinates of the nicotinic acetylcholine receptor as a template to determine details about the zinc binding site (PMID:18197653)
• Significant matching effects were found for polymorphisms at the DRD2, GABRA6 and GABRB2 gene. In addition, a trend was found for the OPRM1 polymorphism. (PMID:19523047)
• Report interaction of androsterone and progesterone with inhibitory ligand-gated ion channels: a patch clamp study. (PMID:19705103)
• Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene may have a role in psychotic disorders (PMID:19763268)
• findings highlight the importance of GABRB2 in neuropsychiatric disease aetiology, with respect to haplotype association, as well as reduction of and temporal effects on gene expression in both schizophrenia and bipolar disorder (PMID:19909288)
• analysis of a recombination hotspot in a schizophrenia-associated region of GABRB2 (PMID:20221451)
• The results of this study pointed to the occurrence of imprinting in the GABRB2 gene and its possible role in the development of schizophrenia. (PMID:20404824)
• Glycosylation of {beta}2 subunits regulates GABAA receptor biogenesis and channel gating. (PMID:20639197)
• The ratios of beta(3)/beta(2) and alpha(5)/alpha(1) subunit protein expression in Angelman syndrome cortex were significantly decreased when compared with controls. (PMID:20692323)
• mRNA expression of Gaba(A)beta2 receptor subunit, which preferentially assembles with alpha1 receptor subunits, is also 20% lower in layers 3 and 4 of the dorsolateral prefrontal cortex. (PMID:20843900)
• GABRA receptor beta2 subunit is not involved in amygdala hyperexcitability of patients with temporal lobe epilepsy. (PMID:20848605)
• A novel pol III-dependent non-coding RNA that regulates alternative splicing events and possibly neurodegeneration induced by abnormal GABA B function. (PMID:20888417)
• beta2Asp163 and alpha1Arg120 form a state-dependent salt bridge, interacting when GABA is bound to the receptor but not when the receptor is in the unbound state. (PMID:21209255)
• significant involvement of alpha (GABRA6) and beta (GABRB2) subunits of GABA(A) receptor in epilepsy susceptibility in north Indian population (PMID:21420396)
• Drugs of abuse directly modulate activity of human alpha(1)beta(2)gamma(2) GABA(A) receptor. (PMID:21729720)
• Data indicate the selectivity of some selected compounds were assessed in recombinant alpha(1)beta(2)gamma(2)L, alpha(2)beta(1)gamma(2)L, and alpha(5)beta(2)gamma(2)L GABA(A) receptors. (PMID:21751815)
• we identified an even stronger coupling between the two aromatics and for the first time provided direct evidence for the involvement of beta in GABA (PMID:21806616)
• This study demonistrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. (PMID:22206711)
• Mutation of GABA receptor beta2 subunit tyrosine residues in the binding pocket shifts the GABA concentration-response curve; GABA binding rates are reduced by mutation to binding pocket tyrosines. (PMID:23121119)
• Report additive inhibition of human alpha1beta2gamma2 GABAA receptors by mixtures of commonly used drugs of abuse. (PMID:23266428)
• Presented is a full-length alpha(1)beta(2)gamma(2) GABA(A) receptor model optimized for agonists and benzodiazepine allosteric modulators. (PMID:23308109)
• high expression of GABBR2 with a low expression of GABR(A3) may predict a better outcome in non-small cell lung cancer (PMID:23617850)
• These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. (PMID:23638040)
• This study demonstrates altered patterns of N-glycosylation of GABRB2 in the temporal lobe in schizophrenia. (PMID:23917429)
• Our findings underscore the need for further investigation into the mechanisms by which mutations in GABRB2 contribute to neurological and developmental dysfunction. (PMID:25124326)
• Both mRNA and protein of GABAB receptor subunits, GABAB1 and GABAB2, were co-expressed in cultured human RPE cells; GABAB receptors regulate the [Ca2+]i via a pertussis toxin-sensitive Gi/o-protein pathway and a phospholipase C pathway (PMID:25241062)
• Deletion of the N-terminal extension and putative alpha-helix in heteromeric alpha1beta2gamma2 GABAA receptors in the beta2 subunit affected GABA sensitivity and desensitization. (PMID:26016529)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gabrb2a	ENSDARG00000079586
danio_rerio	GABRB2	ENSDARG00000100032
mus_musculus	Gabrb2	ENSMUSG00000007653
rattus_norvegicus	Gabrb2	ENSRNOG00000003680

Paralogs (45): GABRA3 (ENSG00000011677), GABRA1 (ENSG00000022355), CHRNA3 (ENSG00000080644), GABRP (ENSG00000094755), CHRNA4 (ENSG00000101204), GLRA2 (ENSG00000101958), GABRE (ENSG00000102287), CHRNE (ENSG00000108556), GABRA4 (ENSG00000109158), GLRB (ENSG00000109738), GABRR2 (ENSG00000111886), GABRG2 (ENSG00000113327), CHRNB4 (ENSG00000117971), CHRNA2 (ENSG00000120903), CHRNA10 (ENSG00000129749), CHRND (ENSG00000135902), CHRNA1 (ENSG00000138435), GLRA3 (ENSG00000145451), GABRA6 (ENSG00000145863), GLRA1 (ENSG00000145888), GABRR1 (ENSG00000146276), CHRNB3 (ENSG00000147432), CHRNA6 (ENSG00000147434), HTR3B (ENSG00000149305), GABRA2 (ENSG00000151834), CHRNB2 (ENSG00000160716), GABRG1 (ENSG00000163285), GABRB1 (ENSG00000163288), GABRB3 (ENSG00000166206), CHRFAM7A (ENSG00000166664), HTR3A (ENSG00000166736), CHRNA5 (ENSG00000169684), CHRNB1 (ENSG00000170175), CHRNA9 (ENSG00000174343), CHRNA7 (ENSG00000175344), HTR3C (ENSG00000178084), GABRG3 (ENSG00000182256), GABRR3 (ENSG00000183185), HTR3E (ENSG00000186038), HTR3D (ENSG00000186090)

Protein

Protein identifiers

Gamma-aminobutyric acid receptor subunit beta-2 — P47870 (reviewed: P47870)

Alternative names: GABA(A) receptor subunit beta-2

All UniProt accessions (6): A0A6Q8PFU0, A0A6Q8PGD9, A0A6Q8PGT5, B7Z279, E7EV50, P47870

UniProt curated annotations — full annotation on UniProt →

Function. Beta subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain. GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient. Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission. GABAARs containing alpha-1 and beta-2 or -3 subunits exhibit synaptogenic activity; the gamma-2 subunit being necessary but not sufficient to induce rapid synaptic contacts formation. Extrasynaptic beta-2 receptors contribute to the tonic GABAergic inhibition. Beta-containing GABAARs can simultaneously bind GABA and histamine where histamine binds at the interface of two neighboring beta subunits, which may be involved in the regulation of sleep and wakefulness.

Subunit / interactions. Heteropentamer, formed by a combination of alpha (GABRA1-6), beta (GABRB1-3), gamma (GABRG1-3), delta (GABRD), epsilon (GABRE), rho (GABRR1-3), pi (GABRP) and theta (GABRQ) chains, each subunit exhibiting distinct physiological and pharmacological properties. Interacts with UBQLN1. May interact with KIF21B. Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3.

Subcellular location. Postsynaptic cell membrane. Cell membrane. Cytoplasmic vesicle membrane.

Tissue specificity. Isoform 1 and isoform 2 show reduced expression in schizophrenic brain. Isoform 3 shows increased expression in schizophrenic and bipolar disorder brains while isoform 4 shows reduced expression.

Disease relevance. Epileptic encephalopathy, infantile or early childhood, 2 (IECEE2) [MIM:617829] A form of epileptic encephalopathy, a heterogeneous group of severe childhood 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. IECEE2 is an autosomal dominant condition with variable age at seizure onset, ranging from early infancy to 6 years. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Allosterically activated by benzodiazepines. Allosterically activated by the anesthetic etomidate. Inhibited by the antagonist bicuculline. Potentiated by histamine.

Domain organisation. The extracellular domain contributes to synaptic contact formation. GABAARs subunits share a common topological structure: a peptide sequence made up of a long extracellular N-terminal, four transmembrane domains, intracellular or cytoplasmic domain located between the third and the fourth transmembrane domains.

Similarity. Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRB2 sub-subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P47870-2	1, Long, Beta-2L	yes
P47870-1	2, Short, Beta-2S
P47870-3	3, Beta-2S1
P47870-4	4, Beta-2S2

RefSeq proteins (3): NP_000804, NP_001358656, NP_068711 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002289	GABAAb_rcpt	Family
IPR006028	GABAA/Glycine_rcpt	Family
IPR006029	Neurotrans-gated_channel_TM	Domain
IPR006201	Neur_channel	Family
IPR006202	Neur_chan_lig-bd	Domain
IPR018000	Neurotransmitter_ion_chnl_CS	Conserved_site
IPR036719	Neuro-gated_channel_TM_sf	Homologous_superfamily
IPR036734	Neur_chan_lig-bd_sf	Homologous_superfamily
IPR038050	Neuro_actylchol_rec	Homologous_superfamily

Pfam: PF02931, PF02932

Catalyzed reactions (Rhea), 1 shown:

• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (70 total): strand 15, helix 10, sequence variant 9, turn 7, splice variant 6, topological domain 5, binding site 5, transmembrane region 4, glycosylation site 3, signal peptide 1, chain 1, modified residue 1, disulfide bond 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

31 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6X3T	ELECTRON MICROSCOPY	2.55
8VRN	ELECTRON MICROSCOPY	2.57
8SGO	ELECTRON MICROSCOPY	2.65
8SID	ELECTRON MICROSCOPY	2.71
8VQY	ELECTRON MICROSCOPY	2.82
6X40	ELECTRON MICROSCOPY	2.86
8DD2	ELECTRON MICROSCOPY	2.9
8DD3	ELECTRON MICROSCOPY	2.9
9CRS	ELECTRON MICROSCOPY	2.9
6X3X	ELECTRON MICROSCOPY	2.92
9DRX	ELECTRON MICROSCOPY	2.95
8SI9	ELECTRON MICROSCOPY	2.98
7T0W	ELECTRON MICROSCOPY	3
7T0Z	ELECTRON MICROSCOPY	3
9CXA	ELECTRON MICROSCOPY	3.04
6X3S	ELECTRON MICROSCOPY	3.12
9CRV	ELECTRON MICROSCOPY	3.18
9CT0	ELECTRON MICROSCOPY	3.19
6X3Z	ELECTRON MICROSCOPY	3.23
6X3W	ELECTRON MICROSCOPY	3.3
9CXC	ELECTRON MICROSCOPY	3.3
9CXB	ELECTRON MICROSCOPY	3.33
9CSB	ELECTRON MICROSCOPY	3.34
9CTV	ELECTRON MICROSCOPY	3.36
9CXD	ELECTRON MICROSCOPY	3.36
6X3U	ELECTRON MICROSCOPY	3.5
6X3V	ELECTRON MICROSCOPY	3.5
9CTP	ELECTRON MICROSCOPY	3.62
9CTJ	ELECTRON MICROSCOPY	3.74
6D6T	ELECTRON MICROSCOPY	3.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P47870-F1	76.65	0.55

Antibody-complex structures (SAbDab): 29 — 6D6T, 6D6U, 6X3S, 6X3T, 6X3U, 6X3V, 6X3W, 6X3X, 6X3Z, 6X40, 7T0W, 7T0Z, 8DD2, 8DD3, 8SGO, 8SI9, 8SID, 8VQY, 8VRN, 9CRS, 9CRV, 9CT0, 9CTJ, 9CTP, 9CTV (+4 more)

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): 121 (in chain b); 180–181 (in chain b); 181; 226; 226 (in chain b)

Post-translational modifications (1): 441

Disulfide bonds (1): 160–174

Glycosylation sites (3): 32, 104, 173

Mutagenesis-validated functional residues (1):

Position	Phenotype
389	displays reduced current rundown following repeated receptor activation.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1236394	Signaling by ERBB4
R-HSA-977443	GABA receptor activation

MSigDB gene sets: 420 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, TGCGCANK_UNKNOWN, GOBP_SYNAPSE_ASSEMBLY, MORF_BRCA1, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GCAAGGA_MIR502, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_GAMMA_AMINOBUTYRIC_ACID_SIGNALING_PATHWAY, GOBP_NEUROGENESIS, MEF2_02, MORF_RAD51L3

GO Biological Process (14): gamma-aminobutyric acid signaling pathway (GO:0007214), chemical synaptic transmission (GO:0007268), synaptic transmission, GABAergic (GO:0051932), inner ear receptor cell development (GO:0060119), innervation (GO:0060384), cellular response to histamine (GO:0071420), cochlea development (GO:0090102), chloride transmembrane transport (GO:1902476), inhibitory synapse assembly (GO:1904862), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), monoatomic ion transmembrane transport (GO:0034220), neuron development (GO:0048666), regulation of postsynaptic membrane potential (GO:0060078)

GO Molecular Function (9): GABA-A receptor activity (GO:0004890), chloride channel activity (GO:0005254), GABA-gated chloride ion channel activity (GO:0022851), transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential (GO:1904315), transmembrane signaling receptor activity (GO:0004888), monoatomic ion channel activity (GO:0005216), extracellular ligand-gated monoatomic ion channel activity (GO:0005230), GABA receptor activity (GO:0016917), signaling receptor activity (GO:0038023)

GO Cellular Component (13): plasma membrane (GO:0005886), cytoplasmic vesicle membrane (GO:0030659), chloride channel complex (GO:0034707), dendritic spine (GO:0043197), postsynaptic membrane (GO:0045211), extracellular exosome (GO:0070062), GABA-ergic synapse (GO:0098982), postsynaptic specialization membrane (GO:0099634), GABA-A receptor complex (GO:1902711), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202), synaptic membrane (GO:0097060)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	1
Neurotransmitter receptors and postsynaptic signal transmission	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GABA receptor activity	2
transmitter-gated monoatomic ion channel activity	2
postsynapse	2
synaptic membrane	2
synapse	2
cell-cell signaling	1
anterograde trans-synaptic signaling	1
chemical synaptic transmission	1
neuron development	1
inner ear receptor cell differentiation	1
nerve development	1
multicellular organismal process	1
response to histamine	1
cellular response to nitrogen compound	1
inner ear development	1
anatomical structure development	1
chloride transport	1
monoatomic anion transmembrane transport	1
synapse assembly	1
transport	1
monoatomic anion transport	1
inorganic anion transport	1
monoatomic ion transport	1
transmembrane transport	1
neuron differentiation	1
cell development	1
regulation of membrane potential	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
chloride channel activity	1
ligand-gated monoatomic anion channel activity	1
regulation of postsynaptic membrane potential	1
signaling receptor activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
ligand-gated monoatomic ion channel activity	1
transmembrane signaling receptor activity	1
molecular transducer activity	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2162 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GABRB2	ALDH5A1	P51649	822
GABRB2	GAD1	Q99259	656
GABRB2	HTR2A	P28223	615
GABRB2	DRD4	P21917	609
GABRB2	DAOA	P59103	608
GABRB2	DRD3	P35462	607
GABRB2	TRAK2	O60296	588
GABRB2	DTNBP1	Q96EV8	580
GABRB2	DRD1	P21728	569
GABRB2	PPP3CC	P48454	567
GABRB2	GABRG2	P18507	566
GABRB2	CLINT1	Q14677	559
GABRB2	GABBR2	O75899	558
GABRB2	SCN1A	P35498	549
GABRB2	SCN1B	Q07699	547

IntAct

5 interactions, top by confidence:

A	B	Type	Score
GABRA1	GABRG2	psi-mi:“MI:0915”(physical association)	0.550
GABRB2	Arhgap32	psi-mi:“MI:0915”(physical association)	0.510
GABRB2	GABRB3	psi-mi:“MI:0914”(association)	0.350

BioGRID (19): GABRB3 (Affinity Capture-MS), ARHGEF25 (Affinity Capture-MS), GABRB2 (Affinity Capture-Western), GABRB2 (Affinity Capture-MS), TRAK2 (Two-hybrid), TRAK2 (Affinity Capture-Western), GABRB2 (Reconstituted Complex), ARHGEF25 (Affinity Capture-MS), GABRB3 (Affinity Capture-MS), GABRB2 (Affinity Capture-MS), TTN (Cross-Linking-MS (XL-MS)), GABRB2 (Affinity Capture-MS), GABRB2 (Cross-Linking-MS (XL-MS)), DYNC1H1 (Affinity Capture-MS), HUWE1 (Affinity Capture-MS)

ESM2 similar proteins: D1LYT2, O94925, P08219, P08220, P0C2W5, P10063, P10064, P14867, P15431, P16305, P18505, P18507, P18508, P19019, P19150, P19969, P20236, P21548, P22300, P22723, P23574, P23576, P24045, P26048, P26049, P27681, P28472, P28473, P30191, P31644, P34903, P47869, P47870, P50571, P62812, P62813, P63079, P63080, P63137, P63138

Diamond homologs: A0A1S4H2E2, A8MPY1, D1LYT2, G5EBR3, O14764, O75311, O93430, P0C2W5, P15431, P18505, P18506, P19019, P20781, P22771, P22933, P23416, P24045, P25123, P28472, P47870, P48167, P48168, P63079, P63080, P63137, P63138, Q08832, Q61603, Q75NA5, Q7TNC8, Q94900, Q9BLY8, Q9GJS9, Q9V9Y4, F1R8P4, O00591, O09028, O18276, P07727, P08219

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
AKT	“up-regulates activity”	GABRB2	phosphorylation
GABRB2	“form complex”	“GABA-A (a4-b2-d) receptor”	binding
GABRB2	“form complex”	“GABA-A (a6-b2-d) receptor”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	34
Uncertain significance	212
Likely benign	247
Benign	69

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1057864	NM_001371727.1(GABRB2):c.755C>T (p.Pro252Leu)	Pathogenic
1177964	NM_001371727.1(GABRB2):c.911C>T (p.Ala304Val)	Pathogenic
1392511	NM_001371727.1(GABRB2):c.981C>G (p.Asn327Lys)	Pathogenic
161444	NM_001371727.1(GABRB2):c.236T>C (p.Met79Thr)	Pathogenic
2201161	NM_001371727.1(GABRB2):c.373G>A (p.Asp125Asn)	Pathogenic
265165	NM_001371727.1(GABRB2):c.845T>C (p.Val282Ala)	Pathogenic
2734811	NM_001371727.1(GABRB2):c.878G>C (p.Arg293Pro)	Pathogenic
3635564	NM_001371727.1(GABRB2):c.851C>T (p.Thr284Ile)	Pathogenic
3893240	NM_001371727.1(GABRB2):c.542A>T (p.Tyr181Phe)	Pathogenic
418957	NM_001371727.1(GABRB2):c.737T>C (p.Ile246Thr)	Pathogenic
451524	NM_001371727.1(GABRB2):c.899C>T (p.Pro300Leu)	Pathogenic
487680	NM_001371727.1(GABRB2):c.859A>C (p.Thr287Pro)	Pathogenic
487681	NM_001371727.1(GABRB2):c.908A>G (p.Lys303Arg)	Pathogenic
487682	NM_001371727.1(GABRB2):c.730T>C (p.Tyr244His)	Pathogenic
487683	NM_001371727.1(GABRB2):c.830T>C (p.Leu277Ser)	Pathogenic
647339	NM_001371727.1(GABRB2):c.895A>T (p.Ile299Phe)	Pathogenic
972959	NM_001371727.1(GABRB2):c.910G>A (p.Ala304Thr)	Pathogenic
1009793	NM_001371727.1(GABRB2):c.151C>G (p.Leu51Val)	Likely pathogenic
1333488	NM_001371727.1(GABRB2):c.627G>T (p.Gln209His)	Likely pathogenic
1338859	NM_001371727.1(GABRB2):c.754C>T (p.Pro252Ser)	Likely pathogenic
1342899	NM_001371727.1(GABRB2):c.857C>T (p.Thr286Ile)	Likely pathogenic
1437389	NM_001371727.1(GABRB2):c.838A>G (p.Thr280Ala)	Likely pathogenic
1464197	NM_001371727.1(GABRB2):c.672T>A (p.Phe224Leu)	Likely pathogenic
1499049	NM_001371727.1(GABRB2):c.901T>C (p.Tyr301His)	Likely pathogenic
1803031	NM_001371727.1(GABRB2):c.929T>C (p.Met310Thr)	Likely pathogenic
2002098	NM_001371727.1(GABRB2):c.907A>G (p.Lys303Glu)	Likely pathogenic
2005333	NM_001371727.1(GABRB2):c.228A>T (p.Glu76Asp)	Likely pathogenic
2125918	NM_001371727.1(GABRB2):c.878G>A (p.Arg293Gln)	Likely pathogenic
224810	NM_001371727.1(GABRB2):c.754C>G (p.Pro252Ala)	Likely pathogenic
2556123	NM_001371727.1(GABRB2):c.238G>C (p.Asp80His)	Likely pathogenic

SpliceAI

1668 predictions. Top by Δscore:

Variant	Effect	Δscore
5:161294424:TCCAT:T	acceptor_gain	1.0000
5:161294425:CCAT:C	acceptor_gain	1.0000
5:161294425:CCATC:C	acceptor_gain	1.0000
5:161294426:CAT:C	acceptor_gain	1.0000
5:161294426:CATC:C	acceptor_gain	1.0000
5:161294427:AT:A	acceptor_gain	1.0000
5:161294428:TC:T	acceptor_loss	1.0000
5:161294429:C:CC	acceptor_gain	1.0000
5:161331126:TCCT:T	acceptor_loss	1.0000
5:161331128:C:CC	acceptor_gain	1.0000
5:161331129:T:C	acceptor_loss	1.0000
5:161410973:A:AC	donor_gain	1.0000
5:161410974:C:CC	donor_gain	1.0000
5:161410974:CAG:C	donor_gain	1.0000
5:161410974:CAGCT:C	donor_gain	1.0000
5:161411056:TT:T	acceptor_gain	1.0000
5:161411058:C:CC	acceptor_gain	1.0000
5:161459619:CAGA:C	donor_loss	1.0000
5:161459620:AGAC:A	donor_loss	1.0000
5:161459621:GACCT:G	donor_loss	1.0000
5:161459622:A:AG	donor_loss	1.0000
5:161459623:CC:C	donor_loss	1.0000
5:161459840:TAATC:T	acceptor_gain	1.0000
5:161459841:AATC:A	acceptor_gain	1.0000
5:161459843:TC:T	acceptor_gain	1.0000
5:161459844:CCTG:C	acceptor_gain	1.0000
5:161459853:G:C	acceptor_gain	1.0000
5:161459853:G:GC	acceptor_gain	1.0000
5:161545223:TCA:T	donor_loss	1.0000
5:161545224:CACC:C	donor_loss	1.0000

AlphaMissense

3387 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:161294101:A:G	W507R	1.000
5:161294101:A:T	W507R	1.000
5:161294133:G:C	P496R	1.000
5:161294133:G:T	P496Q	1.000
5:161294145:C:G	R492P	1.000
5:161294146:G:T	R492S	1.000
5:161294157:T:A	D488V	1.000
5:161294157:T:C	D488G	1.000
5:161294157:T:G	D488A	1.000
5:161294158:C:G	D488H	1.000
5:161330979:G:C	N327K	1.000
5:161330979:G:T	N327K	1.000
5:161330983:A:T	V326D	1.000
5:161330989:G:T	A324D	1.000
5:161330990:C:G	A324P	1.000
5:161330993:A:G	Y323H	1.000
5:161330994:T:A	E322D	1.000
5:161330994:T:G	E322D	1.000
5:161330996:C:T	E322K	1.000
5:161330998:A:G	L321P	1.000
5:161331001:A:C	L320R	1.000
5:161331001:A:G	L320P	1.000
5:161331001:A:T	L320H	1.000
5:161331004:G:T	A319D	1.000
5:161331009:G:C	F317L	1.000
5:161331009:G:T	F317L	1.000
5:161331011:A:G	F317L	1.000
5:161331021:A:C	F313L	1.000
5:161331021:A:T	F313L	1.000
5:161331023:A:G	F313L	1.000

dbSNP variants (sampled 300 via entrez): RS1000003929 (5:161533758 A>T), RS1000008969 (5:161360602 A>C), RS1000011234 (5:161341127 C>T), RS1000016715 (5:161366948 A>G), RS1000025113 (5:161494778 A>T), RS1000052699 (5:161446827 A>G), RS1000062298 (5:161410553 A>T), RS1000065552 (5:161535800 G>A,C,T), RS1000068848 (5:161311806 A>G), RS1000074527 (5:161317525 C>A), RS1000080806 (5:161403695 A>G), RS1000084071 (5:161529268 A>G), RS1000084371 (5:161360482 TTCTC>T,TTC,TTCTCTC), RS1000094983 (5:161318598 C>T), RS1000095873 (5:161488366 C>G,T)

Disease associations

OMIM: gene MIM:600232 | disease phenotypes: MIM:617829, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy 92	Definitive	Autosomal dominant
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (6): intellectual disability (MONDO:0001071), developmental and epileptic encephalopathy 92 (MONDO:0020631), prostate cancer (MONDO:0008315), premenstrual dysphoric disorder (MONDO:1010182), schizophrenia (MONDO:0005090), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (3): Familial prostate cancer (Orphanet:1331), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Reduced tendon reflexes
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005713_2	Plasma neurofilament light levels	7.000000e-06
GCST008512_15	Multisite chronic pain	5.000000e-08
GCST008768_3	Perceived intensity of sweet substances	4.000000e-06
GCST010105_91	Nicotine dependence symptom count	7.000000e-06
GCST012189_8	Systolic blood pressure and diastolic blood pressure (bivariate analysis)	8.000000e-06
GCST012332_70	Multisite chronic pain	8.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0010100	multisite chronic pain
EFO:0009262	nicotine dependence symptom count
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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 (17): CHEMBL1907597 (PROTEIN COMPLEX), CHEMBL1920 (SINGLE PROTEIN), CHEMBL2093872 (PROTEIN COMPLEX GROUP), CHEMBL2095172 (PROTEIN COMPLEX), CHEMBL2109244 (PROTEIN COMPLEX GROUP), CHEMBL2111339 (PROTEIN COMPLEX), CHEMBL2111370 (PROTEIN COMPLEX), CHEMBL2111413 (PROTEIN COMPLEX), CHEMBL3885571 (PROTEIN COMPLEX), CHEMBL3885572 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

47 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 477,934 (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
CHEMBL190461	CANNABIDIOL	4	26,379
CHEMBL1082407	ENZALUTAMIDE	4	9,652
CHEMBL12	DIAZEPAM	4	92,281
CHEMBL1544	LIOTHYRONINE	4	23,700
CHEMBL1568698	GANAXOLONE	4	1,657
CHEMBL207538	BREXANOLONE	4	1,585
CHEMBL3183409	APALUTAMIDE	4	4,076
CHEMBL407	FLUMAZENIL	4	7,150
CHEMBL452	CLONAZEPAM	4	33,297
CHEMBL13280	FLUNITRAZEPAM	4	11,549
CHEMBL1521	ZALEPLON	4	9,958
CHEMBL1983350	STIRIPENTOL	4	2,890
CHEMBL4105630	ZURANOLONE	4	290
CHEMBL526	PROPOFOL	4	28,835
CHEMBL661	ALPRAZOLAM	4	130,677
CHEMBL681	ETOMIDATE	4	8,462
CHEMBL911	ZOLPIDEM	4	17,821
CHEMBL1522	ESZOPICLONE	4	6,548
CHEMBL448	PENTOBARBITAL	4	49,933
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL1064	SIMVASTATIN	4
CHEMBL1106	EPINASTINE	4
CHEMBL146095	GLAFENINE	4
CHEMBL222559	TIPRANAVIR	4
CHEMBL297302	BENPERIDOL	4
CHEMBL3187365	ASENAPINE	4
CHEMBL408	TROGLITAZONE	4
CHEMBL42	CLOZAPINE	4
CHEMBL515	CHLORAMBUCIL	4
CHEMBL601719	CRIZOTINIB	4

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2229944	GABRB2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — GABA_A receptors

Binding affinities (BindingDB)

192 measured of 208 human assays (211 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[7-chloro-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol	KI	0.27 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-4-fluoro-phenol	KI	0.36 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
4-fluoro-3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]phenol	KI	0.38 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
(5S)-8,9-dichloro-7-(2-fluoro-5-hydroxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one	KI	0.39 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
8,9-dichloro-7-(2-fluoro-5-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one	KI	0.39 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-2,4-difluoro-phenol	KI	0.4 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
6-chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one	KI	0.44 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
6,7-dichloro-5-(2,6-difluoro-3-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one	KI	0.46 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
Halcion	KI	0.68 nM
8,9-dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one	KI	0.85 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
[7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]-(3-methoxyazetidin-1-yl)methanone	KI	0.85 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
3-[7-chloro-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol	KI	0.86 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
4-fluoro-3-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]phenol	KI	0.99 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
[7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone	KI	1.04 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
(5S)-8,9-dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one	KI	1.3 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
[7,8-dichloro-6-(2-fluoro-5-hydroxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone	KI	1.4 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
8-chloro-7-(2-fluoro-5-hydroxy-phenyl)-9-(trifluoromethyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one	KI	1.54 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol	KI	2.07 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
2,4-difluoro-3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]phenol	KI	2.12 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol	KI	2.32 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
5-chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol	KI	2.8 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol	KI	3.08 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol	KI	3.25 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
6-[[3-(5-chloro-2-pyridinyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-N-(oxan-4-yl)pyridazine-3-carboxamide	KI	3.4 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
5-chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]pyridin-2-ol	KI	3.63 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
(4S)-7-chloro-N-cyclopropyl-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide	KI	4.4 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
(4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-N-isopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide	KI	4.7 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol	KI	5.02 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
[(4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzo diazepin-2-yl]-(3-fluoroazetidin-1-yl)methanone	KI	5.51 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
[(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-3a,4-dihydro-1H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone	KI	8.25 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-2,4-dimethyl-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine	KI	8.3 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
azetidin-1-yl-[(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]methanone	KI	8.5 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
6-[(10S)-6-chloro-10-methyl-5-(trifluoromethyl)-1,9,12-triazatetracyclo[9.6.0.02,7.013,17]heptadeca-2(7),3,5,8,11,13	KI	8.6 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
azetidin-1-yl-[(4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-2-yl]methanone	KI	8.77 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
[(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone	KI	9.2 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
RO-154513	KI	10 nM
(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-4-methyl-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide	KI	15.2 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]pyridin-2-ol	KI	20.9 nM	US-12344614: Benzodiazepine derivatives as GABA a GAMMA1 PAM
[(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone	KI	23.2 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
(3-hydroxyazetidin-1-yl)-[(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]methanone	KI	23.9 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
[(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoroethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone	KI	29 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
(7,8-dichloro-6-(2-fluorophenyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-2-yl)(3-methoxyazetidin-1-yl)methanone	KI	35.1 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
6-[(5-methyl-3-pyridin-3-yl-1,2-oxazol-4-yl)methoxy]-N-(oxan-4-yl)pyridazine-3-carboxamide	KI	35.6 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
azetidin-1-yl-[(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]methanone	KI	38.1 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
3-[(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]oxazolidin-2-one	KI	39.1 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
(4S)-7-chloro-6-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide	KI	40.8 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
1-[(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-3-methyl-urea	KI	49.9 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
(4S)-7-chloro-6-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide	KI	65.1 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
(4S)-7-chloro-6-(3-fluoro-2-pyridyl)-N-(2-hydroxy-2-methyl-propyl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide	KI	70.4 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-imidazo[1,2-a][1,4]benzodiazepine	KI	94.5 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM

ChEMBL bioactivities

1085 potent at pChembl≥5 of 1291 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.30	Ki	0.05	nM	PHENAZEPAM
10.22	Ki	0.06	nM	PHENAZEPAM
10.00	IC50	0.1	nM	CHEMBL454349
9.92	Ki	0.12	nM	CHEMBL487686
9.92	Ki	0.12	nM	CHEMBL488283
9.92	Ki	0.12	nM	CHEMBL469477
9.92	Ki	0.12	nM	PHENAZEPAM
9.85	Ki	0.14	nM	CHEMBL487687
9.82	Ki	0.15	nM	CHEMBL3274851
9.80	IC50	0.16	nM	CHEMBL309517
9.77	Ki	0.17	nM	CHEMBL50763
9.70	IC50	0.2	nM	CHEMBL4747460
9.66	Ki	0.22	nM	CHEMBL48403
9.62	IC50	0.24	nM	CHEMBL79037
9.59	Ki	0.26	nM	CHEMBL3274851
9.57	Ki	0.27	nM	CHEMBL381059
9.55	Ki	0.28	nM	CHEMBL3274851
9.52	Ki	0.3	nM	CHEMBL290036
9.52	Ki	0.3	nM	CHEMBL49888
9.42	Ki	0.38	nM	CHEMBL471551
9.41	Ki	0.39	nM	CHEMBL487685
9.40	IC50	0.3981	nM	CGS-8216
9.40	Ki	0.4	nM	CHEMBL1451229
9.40	IC50	0.4	nM	CHEMBL1271047
9.35	Ki	0.45	nM	CHEMBL2348441
9.34	IC50	0.46	nM	CHEMBL78730
9.31	IC50	0.49	nM	CHEMBL76263
9.30	Ki	0.5	nM	CHEMBL1451229
9.30	IC50	0.5	nM	CHEMBL5266498
9.30	IC50	0.5	nM	CHEMBL5290464
9.30	IC50	0.5	nM	CHEMBL5280240
9.30	IC50	0.5	nM	CHEMBL49141
9.30	IC50	0.5	nM	CHEMBL1518572
9.29	Ki	0.51	nM	CHEMBL520411
9.29	Ki	0.51	nM	CHEMBL50763
9.28	Ki	0.53	nM	CHEMBL488284
9.22	IC50	0.6026	nM	CGS-9896
9.22	IC50	0.6	nM	CHEMBL419096
9.22	Ki	0.6	nM	ALPRAZOLAM
9.22	Ki	0.6	nM	CHEMBL475204
9.22	Ki	0.6	nM	CHEMBL1451229
9.22	Ki	0.6	nM	CHEMBL3246832
9.22	Ki	0.6	nM	CHEMBL5179977
9.17	Ki	0.68	nM	PHENAZEPAM
9.15	Ki	0.7	nM	CHEMBL3246832
9.15	Ki	0.7	nM	CHEMBL290036
9.12	IC50	0.76	nM	CHEMBL540583
9.10	IC50	0.79	nM	CHEMBL77226
9.10	Ki	0.8	nM	ALPRAZOLAM
9.10	Ki	0.8	nM	CHEMBL5192472

PubChem BioAssay actives

1070 with measured affinity, of 3960 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
1,4,5,6-tetrahydropyrimidine-5-carboxylic acid	1184360: Agonist activity at human GABAAalpha1beta2gamma2S receptor expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	<0.0001	uM
6-amino-2-methylpyridine-3-carboxylic acid	1184360: Agonist activity at human GABAAalpha1beta2gamma2S receptor expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	<0.0001	uM
piperidine-4-carboxylic acid	1184360: Agonist activity at human GABAAalpha1beta2gamma2S receptor expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	<0.0001	uM
2-(4-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-3-one	40988: Inhibition on Benzodiazepine receptor	ic50	0.0001	uM
7-bromo-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one	1889907: Displacement of [3H]flunitrazepam from human recombinant alpha2beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0001	uM
7-bromo-5-(2-chlorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one	1889906: Displacement of [3H]flunitrazepam from human recombinant alpha1beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0001	uM
6-benzyl-3-pentanoyl-1H-quinolin-4-one	343134: Displacement of [3H]flumazenil from human recombinant GABAA alpha-1-beta-2-gamma-2S receptor expressed in HEK293 cells	ki	0.0001	uM
6-benzyl-3-butanoyl-1H-quinolin-4-one	343134: Displacement of [3H]flumazenil from human recombinant GABAA alpha-1-beta-2-gamma-2S receptor expressed in HEK293 cells	ki	0.0001	uM
3-pentanoyl-6-(pyridin-3-ylmethyl)-1H-quinolin-4-one	343134: Displacement of [3H]flumazenil from human recombinant GABAA alpha-1-beta-2-gamma-2S receptor expressed in HEK293 cells	ki	0.0001	uM
3-pentanoyl-6-(pyridin-2-ylmethyl)-1H-quinolin-4-one	343134: Displacement of [3H]flumazenil from human recombinant GABAA alpha-1-beta-2-gamma-2S receptor expressed in HEK293 cells	ki	0.0001	uM
[7-chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4H-imidazo[1,5-a]quinoxalin-5-yl]-morpholin-4-ylmethanone	72905: Displacement of [3H]flunitrazepam from GABA-A receptor alpha-1-beta-2-gamma-2 subunits expressed in Sf9 cells	ki	0.0002	uM
[3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4H-imidazo[1,5-a]quinoxalin-5-yl]-morpholin-4-ylmethanone	72906: Displacement of [3H]Flunitrazepam from GABA-A receptor alpha-1-beta-2-gamma-2 subunits expressed in Sf9 cells	ki	0.0002	uM
ethyl 4-(methoxymethyl)-5-phenylmethoxy-9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0002	uM
Flumazenil	1798656: Radioligand Binding Assay from Article 10.1021/jm800889m: “Structural Requirements for Eszopiclone and Zolpidem Binding to the gamma-Aminobutyric Acid Type-A (GABAA) Receptor Are Different.”	ki	0.0002	uM
[3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-fluoro-4H-imidazo[1,5-a]quinoxalin-5-yl]-morpholin-4-ylmethanone	72906: Displacement of [3H]Flunitrazepam from GABA-A receptor alpha-1-beta-2-gamma-2 subunits expressed in Sf9 cells	ki	0.0003	uM
ethyl 6-benzyl-4-oxo-1H-quinoline-3-carboxylate	343134: Displacement of [3H]flumazenil from human recombinant GABAA alpha-1-beta-2-gamma-2S receptor expressed in HEK293 cells	ki	0.0003	uM
[3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4H-imidazo[1,5-a]quinoxalin-5-yl]-phenylmethanone	72906: Displacement of [3H]Flunitrazepam from GABA-A receptor alpha-1-beta-2-gamma-2 subunits expressed in Sf9 cells	ki	0.0003	uM
8-bromo-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine	1889909: Displacement of [3H]flunitrazepam from human recombinant alpha5beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0004	uM
ethyl 4-methyl-5-propan-2-yloxy-9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0004	uM
2-phenyl-3aH-pyrazolo[4,3-c]quinolin-3-one	40988: Inhibition on Benzodiazepine receptor	ic50	0.0004	uM
3-pentanoyl-6-(pyridin-4-ylmethyl)-1H-quinolin-4-one	343134: Displacement of [3H]flumazenil from human recombinant GABAA alpha-1-beta-2-gamma-2S receptor expressed in HEK293 cells	ki	0.0004	uM
6-ethyl-3-pentanoyl-1H-quinolin-4-one	343134: Displacement of [3H]flumazenil from human recombinant GABAA alpha-1-beta-2-gamma-2S receptor expressed in HEK293 cells	ki	0.0004	uM
3-iodo-5-oxido-N-(pyridin-3-ylmethyl)pyrazolo[5,1-c][1,2,4]benzotriazin-5-ium-8-amine	739949: Displacement of [3H]Ro15-1788 from recombinant GABA-A alpha1beta2gamma2 receptor benzodiazepine binding site (unknown origin) after 1 hr	ki	0.0004	uM
ethyl 4-(methoxymethyl)-6-phenylmethoxy-9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0005	uM
ethyl 4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0005	uM
ethyl 6-methoxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0005	uM
ethyl 4-(methoxymethyl)-6-propoxy-9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0005	uM
ethyl 6-hydroxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0005	uM
6-benzyl-3-(2-cyclopentylacetyl)-1H-quinolin-4-one	343134: Displacement of [3H]flumazenil from human recombinant GABAA alpha-1-beta-2-gamma-2S receptor expressed in HEK293 cells	ki	0.0005	uM
3-pentanoyl-6-(2-phenylethyl)-1H-quinolin-4-one	343134: Displacement of [3H]flumazenil from human recombinant GABAA alpha-1-beta-2-gamma-2S receptor expressed in HEK293 cells	ki	0.0005	uM
8-bromo-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine	1889909: Displacement of [3H]flunitrazepam from human recombinant alpha5beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0006	uM
8-ethynyl-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine	1889909: Displacement of [3H]flunitrazepam from human recombinant alpha5beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0006	uM
6-(2-chlorophenyl)-8-ethynyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine	1889907: Displacement of [3H]flunitrazepam from human recombinant alpha2beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0006	uM
Alprazolam	1889907: Displacement of [3H]flunitrazepam from human recombinant alpha2beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0006	uM
2-(4-chlorophenyl)-3aH-pyrazolo[4,3-c]quinolin-3-one	40988: Inhibition on Benzodiazepine receptor	ic50	0.0006	uM
5-[[3-(1,3-benzodioxol-5-yl)-6-iminopyridazin-1-yl]methyl]-1,2-thiazol-3-one;hydrobromide	72153: Affinity for gamma-aminobutyric-acid A receptor measured by its ability to displace [3H]gabazine antagonist from rat brain preparations.	ic50	0.0008	uM
propan-2-yl 16-(methoxymethyl)-3,6,11,14-tetrazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2,4,6,8,12,14,16-octaene-15-carboxylate	1932305: Inhibition of GABAA receptor (unknown origin)	ic50	0.0008	uM
propan-2-yl 4-(methoxymethyl)-6,9,14,21-tetrazapentacyclo[11.8.0.02,10.03,8.015,20]henicosa-1(21),2,4,6,8,10,12,15(20)-octaene-5-carboxylate	1932305: Inhibition of GABAA receptor (unknown origin)	ic50	0.0008	uM
[6-(5-chloro-2-pyridinyl)-7-hydroxypyrrolo[3,4-b]pyrazin-5-yl] 4-methylpiperazine-1-carboxylate	1798656: Radioligand Binding Assay from Article 10.1021/jm800889m: “Structural Requirements for Eszopiclone and Zolpidem Binding to the gamma-Aminobutyric Acid Type-A (GABAA) Receptor Are Different.”	ki	0.0008	uM
propan-2-yl 15-(methoxymethyl)-4-propan-2-yl-5-oxa-10,13-diazatetracyclo[7.7.0.02,6.011,16]hexadeca-1(9),2(6),3,7,11,13,15-heptaene-14-carboxylate	1932305: Inhibition of GABAA receptor (unknown origin)	ic50	0.0008	uM
Clonazepam	239299: Displacement of [3H]flumazenil from bovine benzodiazepine receptor GABA-A channel of brain membranes	ki	0.0008	uM
7-ethynyl-5-(2-fluorophenyl)-1-methyl-3H-1,4-benzodiazepin-2-one	1889909: Displacement of [3H]flunitrazepam from human recombinant alpha5beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0008	uM
15-(methoxymethyl)-14-(5-methyl-1,2-oxazol-3-yl)-4-propan-2-yl-5-oxa-3,10,13-triazatetracyclo[7.7.0.02,6.011,16]hexadeca-1(9),2(6),3,7,11,13,15-heptaene	1932305: Inhibition of GABAA receptor (unknown origin)	ic50	0.0009	uM
3-(2-cyclopentylacetyl)-6-(pyridin-3-ylmethyl)-1H-quinolin-4-one	343134: Displacement of [3H]flumazenil from human recombinant GABAA alpha-1-beta-2-gamma-2S receptor expressed in HEK293 cells	ki	0.0009	uM
ethyl 9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0010	uM
methyl 9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0010	uM
propyl 9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0010	uM
tert-butyl 9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0010	uM
7-chloro-5-methyl-3-(2-phenylethynyl)-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one	1196597: Displacement of [3H]flumazenil from rat cortex GABAA receptor BDZ binding site expressed in HEK293 cells by competition binding assay	ki	0.0010	uM
5-(2-chlorophenyl)-7-ethynyl-1-methyl-3H-1,4-benzodiazepin-2-one	1889907: Displacement of [3H]flunitrazepam from human recombinant alpha2beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0010	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
gamma-Aminobutyric Acid	increases reaction, increases transport, affects binding, decreases reaction, increases activity (+2 more)	12
Valproic Acid	affects cotreatment, increases expression, affects expression	6
trichostatin A	affects cotreatment, increases expression	3
1-(3-chlorophenyl)piperazine	increases activity, decreases activity, increases reaction, affects binding, decreases reaction	2
2,4,2’,4’-tetrachlorobiphenyl	affects binding, increases activity, affects cotreatment, increases reaction, decreases reaction	2
mercuric bromide	increases expression, affects cotreatment	2
loreclezole	increases transport, affects response to substance, increases reaction	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Diazepam	affects binding, increases activity, increases reaction	2
Doxorubicin	decreases expression, affects expression	2
6-methoxyflavone	affects binding, increases activity, increases reaction	1
6-methoxyflavanone	affects binding, increases activity, increases reaction	1
beta-thujone	affects binding, decreases reaction, increases activity	1
1-benzylpiperazine	affects binding, decreases reaction, increases activity	1
carvone	increases reaction, affects binding, increases activity	1
2,5,2’,5’-tetrachlorobiphenyl	affects binding, affects cotreatment, increases activity	1
tetramethylenedisulfotetramine	affects binding, decreases reaction, increases activity, increases reaction	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects binding, decreases reaction, increases activity	1
bromoform	affects activity, affects binding	1
1-(3-trifluoromethylphenyl)piperazine	decreases reaction, increases activity, affects binding	1
menthone	affects binding, increases activity, increases reaction	1
tetrabromobisphenol A	affects binding, affects reaction, increases activity, increases reaction	1
isoborneol	affects binding, increases activity, increases reaction	1
picrotoxinin	affects binding, decreases reaction, increases activity	1
1-(4-chlorophenyl)piperazine	affects binding, decreases reaction, increases activity	1
phenylpiperazine	affects binding, decreases reaction, increases activity	1
2,2’,3,5’,6-pentachlorobiphenyl	affects binding, affects cotreatment, increases activity	1
tert-butylbicyclophosphorothionate	affects binding, decreases reaction	1
1-(2-methoxyphenyl)piperazine	affects binding, decreases reaction, increases activity	1

ChEMBL screening assays

549 unique, capped per target: 463 binding, 81 functional, 4 toxicity, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1816618	Binding	Modulation of GABA Aalpha1beta2 receptor expressed in Xenopus laevis oocytes assessed as potentiation of GABA-induced chloride current at holding potential -70 mV by two-microelectrode voltage clamp technique	Modulation of GABAA-receptors by honokiol and derivatives: subtype selectivity and structure-activity relationship. — J Med Chem
CHEMBL4810229	ADMET	Inhibition of GABA A receptor (unknown origin) at 0.1 to 1 uM	Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor. — J Med Chem
CHEMBL5335653	Toxicity	Antagonist activity at GABA-A (unknown origin)	Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_C0XQ	B’SYS CHO alpha1beta2gamma2 GABA(A)	Spontaneously immortalized cell line	Female
CVCL_C0YP	CHO-K1 GABA(A)R alpha1beta2gamma2L	Spontaneously immortalized cell line	Female
CVCL_C5TV	GABAA1-CHO	Spontaneously immortalized cell line	Female
CVCL_C9E7	B’SYS LTK alpha1beta2gamma2 GABA(A)	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders