GABRA1

Summary

GABRA1 (gamma-aminobutyric acid type A receptor subunit alpha1, HGNC:4075) is a protein-coding gene on chromosome 5q34, encoding Gamma-aminobutyric acid receptor subunit alpha-1 (P14867). Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.

This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene.

Source: NCBI Gene 2554 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epilepsy (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 797 total — 44 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 98
• Druggable target: yes — 60 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001127644

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4075
Approved symbol	GABRA1
Name	gamma-aminobutyric acid type A receptor subunit alpha1
Location	5q34
Locus type	gene with protein product
Status	Approved
Aliases	EJM5
Ensembl gene	ENSG00000022355
Ensembl biotype	protein_coding
OMIM	137160
Entrez	2554

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 16 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000023897, ENST00000393943, ENST00000428797, ENST00000437025, ENST00000519542, ENST00000519621, ENST00000521339, ENST00000522651, ENST00000634335, ENST00000635096, ENST00000635880, ENST00000635916, ENST00000636340, ENST00000636408, ENST00000636573, ENST00000637044, ENST00000637620, ENST00000637827, ENST00000638112, ENST00000638159, ENST00000958929, ENST00000958930

RefSeq mRNA: 5 — MANE Select: NM_001127644 NM_000806, NM_001127643, NM_001127644, NM_001127645, NM_001127648

CCDS: CCDS4357

Canonical transcript exons

ENST00000393943 — 10 exons

Exon	Start	End
ENSE00001132378	161873117	161873337
ENSE00001132396	161854158	161854270
ENSE00001608765	161895666	161895868
ENSE00001746022	161890898	161891050
ENSE00001769364	161848120	161848422
ENSE00003480742	161850796	161850884
ENSE00003651730	161875560	161875642
ENSE00003691884	161882558	161882701
ENSE00003785423	161865721	161865788
ENSE00003849180	161897111	161899971

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 98.83.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 6.7521 / max 717.6807, expressed in 127 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59934	1.5184	92
59937	1.3070	100
59933	1.0894	91
59939	1.0367	75
59938	0.7485	83
59940	0.3291	50
59935	0.3178	70
59932	0.1916	60
59936	0.0983	53
203780	0.0700	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	98.83	gold quality
endothelial cell	CL:0000115	98.23	gold quality
middle temporal gyrus	UBERON:0002771	97.86	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.68	gold quality
superior frontal gyrus	UBERON:0002661	97.27	gold quality
primary visual cortex	UBERON:0002436	97.10	gold quality
postcentral gyrus	UBERON:0002581	96.92	gold quality
parietal lobe	UBERON:0001872	96.45	gold quality
occipital lobe	UBERON:0002021	96.34	gold quality
frontal pole	UBERON:0002795	96.03	gold quality
lateral globus pallidus	UBERON:0002476	95.87	gold quality
prefrontal cortex	UBERON:0000451	95.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.74	gold quality
cerebellar vermis	UBERON:0004720	95.49	gold quality
cerebellum	UBERON:0002037	95.48	gold quality
cerebellar cortex	UBERON:0002129	95.46	gold quality
cerebellar hemisphere	UBERON:0002245	95.38	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.35	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.82	gold quality
frontal cortex	UBERON:0001870	94.72	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.65	gold quality
entorhinal cortex	UBERON:0002728	94.64	gold quality
orbitofrontal cortex	UBERON:0004167	93.56	gold quality
neocortex	UBERON:0001950	93.43	gold quality
right frontal lobe	UBERON:0002810	93.10	gold quality
cerebral cortex	UBERON:0000956	92.43	gold quality
cingulate cortex	UBERON:0003027	92.24	gold quality
anterior cingulate cortex	UBERON:0009835	92.19	gold quality
paraflocculus	UBERON:0005351	90.56	gold quality
telencephalon	UBERON:0001893	88.49	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-98556	yes	443.19
E-MTAB-7316	yes	36.81
E-HCAD-25	yes	35.90
E-GEOD-137537	yes	19.79
E-GEOD-84465	yes	6.71
E-ANND-3	yes	4.55
E-MTAB-6075	no	37.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• modeling of molecular configuration (PMID:12225856)
• using full-length or truncated chimeric subunits it was demonstrated that homologous sequences from alpha 1 are important for assembly of GABA(A) receptors composed of alpha(1), beta(3), and gamma(2) subunits (PMID:12367595)
• a role for tryptophan (Trp) residues at the extracellular end of fourth transmembrane segment(TM4) in anesthetic modulation of GABA(A) receptors. (PMID:12367612)
• Optimal gating is dependent on electrostatic interactions between the negatively charged Asp 57 and Asp 149 residues in extracellular loops 2 and 7, and the positively charged Lys 279 residue in the transmembrane 2-3 linker region of the alpha1-subunit (PMID:12529644)
• Among polymorphic SNPs, significant differences between methamphetamine users and controls are found in the female sample of GABA(A)alpha1 subunit gene, and the novel SNP in the GABA(A)gamma2 subunit gene. No associations were found in the male sample. (PMID:14569258)
• Properties of recombinant GABRA1 receptor vary significantly from one expression system to another most likely due to differences in endogenous modulators. (PMID:14625018)
• GABA acts through GABA(A) receptors containing the alpha(1) subunit on specific striatal GABAergic interneurons and on output neurons of the globus pallidus and substantia nigra pars reticulata. (PMID:14961561)
• The mutated (A294D) GABAA receptor alpha 1 subunit reduces GABA sensitivity of the receptor, increases the deactivation rate and slows desensitization, causing a reduction in channel open time but no change in single channel conductance. (PMID:14996540)
• 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)
• alpha1 and alpha6 subunits immobilize recombinant GABA A receptor in transfected cells (PMID:15196679)
• whole-cell currents and protein expression of heterozygous 1(A322D)2S2S receptors depended on the position of the mutant 1 subunit (PMID:15201329)
• The A322D mutation leads to a severe loss-of-function of the human GABAA receptor by several mechanisms, including reduced surface expression, reduced GABA-sensitivity, and accelerated deactivation. (PMID:16029191)
• The mechanism of reduced total and surface alpha1 subunit expression associated with an aspartate substitution in the GABA-A receptor alpha1 subunit is reported. (PMID:16123039)
• Derepression of GABAAR-alpha1 expression upon downregulation of c-myc represents a unique apoptotic mechanism and a distinct function for the alpha1 subunit, independent of its role as a component of the GABAAR in the plasma membrane. (PMID:16294320)
• Models of GABA(A) receptors composed of alpha1 beta3 gamma2 subunits were generated and were used for predicting putative engineered cross-link sites between the alpha1 and the gamma2 subunit. (PMID:16412095)
• Since the 156T>C variant appears to be not pathogenically relevant, our results suggest that missense, nonsense or splice site mutation in the coding region of the GABRA1 gene is not a major genetic cause of ET in Caucasian subjects. (PMID:16530959)
• 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)
• polymorphisms of the GABAA alpha1 and GABAA alpha6 receptor gene may be associated with the development of alcoholism and the GG genotype of the GABAA alpha1 receptor may cause early onset and a severe type of alcoholism (PMID:16778401)
• association between GABRA1 and alcohol dependence, history of blackouts, age at first drunkenness, and level of response to alcohol (PMID:16792556)
• the prefrontal and temporal cortex of ALS patients, we detected significantly reduced mRNA expression of the alpha1-subunit, while the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) was significantly upregulated in these regions. (PMID:17011586)
• An intrinsic deficiency of GABA(A) receptor endogenous phosphorylation results in an increased lability of GABAergic currents in neurons isolated from epileptogenic human tissue. (PMID:17360668)
• The GABAA receptor alpha1 subunit epilepsy mutation A322D inhibits transmembrane helix formation and causes proteasomal degradation. (PMID:17670950)
• study found mutations of GABRA1, GABRB3, and GABRG2 appear not to play a major role in the development of familial primary dystonia (PMID:17880575)
• In this case of juvenile myoclonic epilepsy , A molecular genetic analysis led to the identification of a polymorphism (T–>C) of the exon of the GABRA1 gene, without aminoacidic exchange. (PMID:17972043)
• 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)
• Using wild type/mutated receptor subunits to identify compounds with anesthetic effect. (PMID:18292428)
• GABAA receptor alpha1-subunit epilepsy mutation A322D results in receptors that are inserted into the plasma membrane but are more rapidly endocytosed by a dynamin and caveolin1-dependent mechanism (PMID:18534981)
• Increased expression of DNMT-3B mRNA and protein in the frontopolar cortex of suicide victims was correlated with increased DNA methylation of the GABAA receptor alpha(1) subunit. (PMID:18639864)
• the Cys-loop receptor aspartate residue in the M3-M4 cytoplasmic loop is required for GABAA receptor assembly (PMID:18723504)
• results suggest that there are likely to be independent, complex contributions from both GABRG1 and GABRA2 to alcoholism vulnerability based on the genotyping of 24 GABRG1 and GABRA2 SNPs in Finnish Caucasian men and Plains Indian men and women. (PMID:18818659)
• Data show that GABRA1 is significantly altered in cerebellum and superior frontal cortex, and significant reductions in parietal cortex in subjects with autism. (PMID:18821008)
• BDNF- and seizure-dependent phosphorylation of STAT3 cause the adenosine 3’,5’-monophosphate (cAMP) response element-binding protein (CREB) family member ICER (inducible cAMP early repressor) to bind with phosphorylated CREB at the Gabra1:CRE site. (PMID:18922788)
• Report interaction of androsterone and progesterone with inhibitory ligand-gated ion channels: a patch clamp study. (PMID:19705103)
• Numerous classes of general anesthetics inhibit etomidate binding to gamma-aminobutyric acid type A (GABAA) receptors (PMID:20083606)
• GABRA1 subunit expression decreases with age in patient with pediatric epilepsy. (PMID:20132297)
• Results show diffuse or focal GABA-A receptor density reduction associated with cognitive defects in systemic lupus erythematosus patients. (PMID:20427410)
• transfected into neurons, the mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy altered the time course of miniature inhibitory postsynaptic current kinetics and reduced miniature inhibitory postsynaptic current amplitudes (PMID:20551311)
• 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)
• In subjects with schizophrenia, mean GABA(A) alpha1 receptor subunit mRNA expression is 17% lower in layers 3 and 4 of the dorsolateral prefrontal cortex. (PMID:20843900)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gabra1	ENSDARG00000068989
mus_musculus	Gabra1	ENSMUSG00000010803
rattus_norvegicus	Gabra1	ENSRNOG00000003512

Paralogs (45): GABRA3 (ENSG00000011677), 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), GABRB2 (ENSG00000145864), 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 alpha-1 — P14867 (reviewed: P14867)

Alternative names: GABA(A) receptor subunit alpha-1

All UniProt accessions (9): A0A0U1RQJ3, A0A0U1RRB2, A0A1B0GU82, A0A1B0GV38, A0A1B0GVW9, E5RHL6, E5RJS3, E5RK60, P14867

UniProt curated annotations — full annotation on UniProt →

Function. Alpha 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. Alpha-1/GABRA1-containing GABAARs are largely synaptic. 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. GABAARs function also as histamine receptor where histamine binds at the interface of two neighboring beta subunits and potentiates GABA response. GABAARs containing alpha, beta and epsilon subunits also permit spontaneous chloride channel activity while preserving the structural information required for GABA-gated openings. Alpha-1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection. Together with rho subunits, may also control neuronal and glial GABAergic transmission in the cerebellum.

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) subunits, each subunit exhibiting distinct physiological and pharmacological properties. Interacts with UBQLN1. Interacts with TRAK1. Interacts with KIF21B. Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3. Interacts with LHFPL4. Interacts with NLGN2. Interacts with SHISA7; interaction leads regulation of GABAAR trafficking, channel deactivation kinetics and pharmacology.

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

Disease relevance. Epilepsy, childhood absence 4 (ECA4) [MIM:611136] A subtype of idiopathic generalized epilepsy characterized by an onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Tonic-clonic seizures often develop in adolescence. Absence seizures may either remit or persist into adulthood. Disease susceptibility is associated with variants affecting the gene represented in this entry. Epilepsy, idiopathic generalized 13 (EIG13) [MIM:611136] A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. Disease susceptibility is associated with variants affecting the gene represented in this entry. Juvenile myoclonic epilepsy 5 (EJM5) [MIM:611136] A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. Disease susceptibility is associated with variants affecting the gene represented in this entry. Developmental and epileptic encephalopathy 19 (DEE19) [MIM:615744] A severe neurologic disorder characterized by onset of seizures in the first months of life and usually associated with EEG abnormalities. Affected infants have convulsive seizures (hemiclonic or generalized) that are often prolonged and triggered by fever. Other seizure types include focal, myoclonic, absence seizures, and drop attacks. Development is normal in the first year of life with later slowing and intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Allosterically activated by benzodiazepines and the anesthetic alphaxalone. Allosterically activated by pentobarbital. Inhibited by the antagonist bicuculline. Potentiated by histamine.

Domain organisation. The extracellular domain contributes to synaptic contact formation. The GABA-binding pockets are located at the interface between neighboring alpha and beta subunits. 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.

Miscellaneous. Functions as a receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site.

Similarity. Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRA1 sub-subfamily.

RefSeq proteins (5): NP_000797, NP_001121115, NP_001121116, NP_001121117, NP_001121120 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001390	GABAAa_rcpt	Family
IPR005431	GABBAa1_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
IPR047024	Gabra-1-6_TM	Domain
IPR047079	GABRA1_ECD	Domain

Pfam: PF02931, PF02932

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (62 total): strand 15, helix 10, sequence variant 6, turn 6, topological domain 5, sequence conflict 5, transmembrane region 4, binding site 3, mutagenesis site 3, glycosylation site 2, signal peptide 1, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

86 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9EQG	ELECTRON MICROSCOPY	2.4
9FAS	ELECTRON MICROSCOPY	2.5
9FFU	ELECTRON MICROSCOPY	2.5
6X3T	ELECTRON MICROSCOPY	2.55
8VRN	ELECTRON MICROSCOPY	2.57
8PET	ELECTRON MICROSCOPY	2.6
9FAJ	ELECTRON MICROSCOPY	2.6
9FAK	ELECTRON MICROSCOPY	2.6
9FGG	ELECTRON MICROSCOPY	2.6
8SGO	ELECTRON MICROSCOPY	2.65
7QNE	ELECTRON MICROSCOPY	2.7
9FG7	ELECTRON MICROSCOPY	2.7
9FG9	ELECTRON MICROSCOPY	2.7
8SID	ELECTRON MICROSCOPY	2.71
7PBZ	ELECTRON MICROSCOPY	2.79
9FAP	ELECTRON MICROSCOPY	2.8
9FFL	ELECTRON MICROSCOPY	2.8
9FFV	ELECTRON MICROSCOPY	2.8
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
9FAQ	ELECTRON MICROSCOPY	2.9
9FG8	ELECTRON MICROSCOPY	2.9
9FGF	ELECTRON MICROSCOPY	2.9
6X3X	ELECTRON MICROSCOPY	2.92
9DRX	ELECTRON MICROSCOPY	2.95
8SI9	ELECTRON MICROSCOPY	2.98
7PC0	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14867-F1	82.21	0.66

Antibody-complex structures (SAbDab): 66 — 6D6T, 6D6U, 6HUG, 6HUJ, 6HUK, 6HUO, 6HUP, 6I53, 6X3S, 6X3T, 6X3U, 6X3V, 6X3W, 6X3X, 6X3Z, 6X40, 7PBD, 7PBZ, 7PC0, 7QNE, 7T0W, 7T0Z, 8DD2, 8DD3, 8PET (+41 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 (3): 94; 157; 273

Disulfide bonds (1): 166–180

Glycosylation sites (2): 38, 138

Mutagenesis-validated functional residues (3):

Position	Phenotype
269	reduced potentiation and activation by the agonist alphaxalone.
273	completely abolishes potentiation and activation by the agonist alphaxalone.
333	reduced potentiation and activation by the agonist alphaxalone.

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: 399 (showing top): AHRARNT_01, RRAGTTGT_UNKNOWN, MODULE_274, GOBP_SYNAPSE_ASSEMBLY, TTTGTAG_MIR520D, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_GAMMA_AMINOBUTYRIC_ACID_SIGNALING_PATHWAY, MORF_RAD51L3, GOBP_CELL_CELL_SIGNALING, PAX8_B, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_CHLORIDE_TRANSPORT, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GOBP_REGULATION_OF_POSTSYNAPTIC_MEMBRANE_POTENTIAL

GO Biological Process (8): gamma-aminobutyric acid signaling pathway (GO:0007214), synaptic transmission, GABAergic (GO:0051932), 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), regulation of postsynaptic membrane potential (GO:0060078)

GO Molecular Function (10): GABA-A receptor activity (GO:0004890), 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), chloride channel activity (GO:0005254), benzodiazepine receptor activity (GO:0008503), GABA receptor activity (GO:0016917), signaling receptor activity (GO:0038023)

GO Cellular Component (14): plasma membrane (GO:0005886), cytoplasmic vesicle membrane (GO:0030659), dendrite membrane (GO:0032590), chloride channel complex (GO:0034707), dendritic spine (GO:0043197), postsynapse (GO:0098794), GABA-ergic synapse (GO:0098982), postsynaptic specialization membrane (GO:0099634), GABA receptor complex (GO:1902710), GABA-A receptor complex (GO:1902711), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

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
dendrite	2
postsynapse	2
synapse	2
cellular anatomical structure	2
synaptic membrane	2
cell-cell signaling	1
chemical synaptic transmission	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
regulation of membrane potential	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
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
neurotransmitter receptor activity	1
transmembrane signaling receptor activity	1
molecular transducer activity	1
membrane	1
cell periphery	1
vesicle membrane	1
cytoplasmic vesicle	1
neuron projection membrane	1
monoatomic ion channel complex	1
neuron spine	1
postsynaptic membrane	1
postsynaptic specialization	1
signaling receptor complex	1

Protein interactions and networks

STRING

2290 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GABRA1	CLCN2	P51788	877
GABRA1	EFHC1	Q5JVL4	812
GABRA1	SLC12A5	Q9H2X9	792
GABRA1	SCN1A	P35498	782
GABRA1	SCN1B	Q07699	747
GABRA1	GAD1	Q99259	742
GABRA1	CACNB4	O00305	726
GABRA1	USP46	P62068	713
GABRA1	CACNA1H	O95180	707
GABRA1	GABBR1	Q9UBS5	705
GABRA1	GRIN2A	Q12879	688
GABRA1	GPHN	Q9NQX3	664
GABRA1	GRIK1	P39086	636
GABRA1	PCDH19	Q8TAB3	636
GABRA1	SCN2A	Q99250	610

IntAct

29 interactions, top by confidence:

A	B	Type	Score
GABRA1	GABRG2	psi-mi:“MI:0915”(physical association)	0.610
GABRA1	GABRG2	psi-mi:“MI:0407”(direct interaction)	0.610
GABRG2	GABRA1	psi-mi:“MI:0914”(association)	0.610
GABRA1	GABRG2	psi-mi:“MI:0915”(physical association)	0.550
	GABRA1	psi-mi:“MI:0915”(physical association)	0.400
GABRA1	CLTCL1	psi-mi:“MI:0915”(physical association)	0.400
GABRA1	GABRG2	psi-mi:“MI:0915”(physical association)	0.320
CDH13	GABRA1	psi-mi:“MI:0403”(colocalization)	0.270
Arfgef2	GABRA1	psi-mi:“MI:0403”(colocalization)	0.270
AKT1	GABRA1	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	GABRA1	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	GABRA1	psi-mi:“MI:2364”(proximity)	0.270
GABRA1	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	GABRA1	psi-mi:“MI:2364”(proximity)	0.270
GABRA1	SPOP	psi-mi:“MI:2364”(proximity)	0.270
GABRA1	EGFR	psi-mi:“MI:2364”(proximity)	0.270
GABRA1	PTPN11	psi-mi:“MI:2364”(proximity)	0.270
GABRA1	TP53	psi-mi:“MI:2364”(proximity)	0.270
GABRA1	PTEN	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (150): GABRA1 (Reconstituted Complex), GABRA1 (Affinity Capture-Western), OS9 (Affinity Capture-Western), HSP90B1 (Affinity Capture-Western), CANX (Affinity Capture-Western), VCP (Affinity Capture-Western), SYVN1 (Affinity Capture-Western), GABRB2 (Affinity Capture-Western), GABRG3 (Affinity Capture-Western), CLTCL1 (Affinity Capture-MS), PRKCG (Affinity Capture-Western), PRKCD (Affinity Capture-Western), GABRA1 (Affinity Capture-MS), GABRB2 (Affinity Capture-MS), GABRG2 (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: A8MPY1, D1LYT2, F1R8P4, G5EBR3, O00591, O09028, O14764, O18276, O75311, O93430, P07727, P08219, P08220, P0C2W5, P10063, P10064, P14867, P15431, P16305, P18505, P18506, P18507, P18508, P19019, P19150, P19969, P20236, P20237, P20781, P21548, P22300, P22723, P22771, P22933, P23415, P23416, P23574, P23576, P24045, P24046

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GABRA1	“form complex”	“GABA-A (a1-b1-g2) receptor”	binding
PCDH19	“up-regulates quantity by stabilization”	GABRA1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	36
Uncertain significance	346
Likely benign	229
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069674	NC_000005.9:g.(?161128494)(161580374_?)del	Pathogenic
127073	NM_001127644.2(GABRA1):c.751G>A (p.Gly251Ser)	Pathogenic
127075	NM_001127644.2(GABRA1):c.917A>C (p.Lys306Thr)	Pathogenic
1349381	NM_001127644.2(GABRA1):c.975C>A (p.Phe325Leu)	Pathogenic
1414135	NM_001127644.2(GABRA1):c.813del (p.Phe272fs)	Pathogenic
149967	GRCh38/hg38 5q33.3-34(chr5:158941354-164386760)x1	Pathogenic
1506120	NM_001127644.2(GABRA1):c.275T>C (p.Phe92Ser)	Pathogenic
1514692	NM_001127644.2(GABRA1):c.755A>G (p.Tyr252Cys)	Pathogenic
1685835	NM_001127644.2(GABRA1):c.559T>G (p.Tyr187Asp)	Pathogenic
2003137	NM_001127644.2(GABRA1):c.830A>G (p.Glu277Gly)	Pathogenic
2020265	NM_001127644.2(GABRA1):c.978_982del (p.Ala327fs)	Pathogenic
2027203	NM_001127644.2(GABRA1):c.1070_1074del (p.Val357fs)	Pathogenic
205524	NM_001127644.2(GABRA1):c.881C>T (p.Thr294Ile)	Pathogenic
217878	NM_001127644.2(GABRA1):c.902G>A (p.Arg301Lys)	Pathogenic
2243209	NM_001127644.2(GABRA1):c.199G>T (p.Glu67Ter)	Pathogenic
2423399	NC_000005.9:g.(?161309544)(161309727_?)del	Pathogenic
242830	NM_001127644.2(GABRA1):c.1200del (p.Lys401fs)	Pathogenic
280804	NM_001127644.2(GABRA1):c.788T>A (p.Met263Lys)	Pathogenic
2922377	NM_001127644.2(GABRA1):c.365G>A (p.Trp122Ter)	Pathogenic
2925385	NM_001127644.2(GABRA1):c.875C>T (p.Thr292Ile)	Pathogenic
2942901	NM_001127644.2(GABRA1):c.839C>A (p.Pro280Gln)	Pathogenic
2950039	NM_001127644.2(GABRA1):c.560-95_598del	Pathogenic
3253005	NM_001127644.2(GABRA1):c.875C>G (p.Thr292Ser)	Pathogenic
3340284	NM_001127644.2(GABRA1):c.865A>C (p.Thr289Pro)	Pathogenic
3341136	NC_000005.10:g.161832946_162532555del	Pathogenic
3342371	NM_001127644.2(GABRA1):c.644T>C (p.Leu215Pro)	Pathogenic
3753872	NM_001127644.2(GABRA1):c.778C>G (p.Pro260Ala)	Pathogenic
4071944	NM_001127644.2(GABRA1):c.918G>T (p.Lys306Asn)	Pathogenic
419523	NM_001127644.2(GABRA1):c.752G>A (p.Gly251Asp)	Pathogenic
4282470	NM_001127644.2(GABRA1):c.853T>C (p.Phe285Leu)	Pathogenic

SpliceAI

1685 predictions. Top by Δscore:

Variant	Effect	Δscore
5:161854144:AT:A	acceptor_gain	1.0000
5:161854145:T:G	acceptor_gain	1.0000
5:161854145:T:TA	acceptor_gain	1.0000
5:161854156:A:AG	acceptor_gain	1.0000
5:161854157:G:GA	acceptor_gain	1.0000
5:161854157:GC:G	acceptor_gain	1.0000
5:161854157:GCT:G	acceptor_gain	1.0000
5:161854157:GCTA:G	acceptor_gain	1.0000
5:161854157:GCTAT:G	acceptor_gain	1.0000
5:161854266:GGGAG:G	donor_gain	1.0000
5:161854267:GGAG:G	donor_gain	1.0000
5:161854267:GGAGG:G	donor_gain	1.0000
5:161854268:GAG:G	donor_gain	1.0000
5:161854268:GAGG:G	donor_gain	1.0000
5:161854269:AG:A	donor_gain	1.0000
5:161854269:AGG:A	donor_loss	1.0000
5:161854270:GG:G	donor_gain	1.0000
5:161854271:G:GG	donor_gain	1.0000
5:161854271:GT:G	donor_loss	1.0000
5:161865719:A:AG	acceptor_gain	1.0000
5:161865720:G:GG	acceptor_gain	1.0000
5:161865720:GA:G	acceptor_gain	1.0000
5:161865720:GAGC:G	acceptor_gain	1.0000
5:161865784:ATATG:A	donor_gain	1.0000
5:161865785:TATG:T	donor_gain	1.0000
5:161865787:TG:T	donor_gain	1.0000
5:161865787:TGGT:T	donor_loss	1.0000
5:161865788:GG:G	donor_gain	1.0000
5:161865788:GGT:G	donor_loss	1.0000
5:161865789:G:GG	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000016966 (5:161865948 A>G), RS1000042064 (5:161883511 A>T), RS1000215969 (5:161897683 G>A,T), RS1000216496 (5:161849084 A>C), RS1000223815 (5:161851573 T>A,C), RS1000240372 (5:161871008 A>T), RS1000244821 (5:161894866 T>G), RS1000270294 (5:161848841 A>G), RS1000278989 (5:161886299 T>G), RS1000295268 (5:161860810 G>A), RS1000324099 (5:161891559 T>A), RS1000382079 (5:161854651 C>A,T), RS1000472744 (5:161865268 A>C,G), RS1000508515 (5:161869292 T>C), RS1000553629 (5:161898950 A>T)

Disease associations

OMIM: gene MIM:137160 | disease phenotypes: MIM:600669, MIM:611136, MIM:615744, MIM:254770, MIM:606904, MIM:604772

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 19	Definitive	Autosomal dominant
epilepsy, idiopathic generalized, susceptibility to, 13	Strong	Autosomal dominant
juvenile myoclonic epilepsy	Supportive	Autosomal dominant
Dravet syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
epilepsy	Definitive	AD

Mondo (9): idiopathic generalized epilepsy (MONDO:0005579), epilepsy, idiopathic generalized, susceptibility to, 13 (MONDO:0012627), developmental and epileptic encephalopathy, 19 (MONDO:0014328), epilepsy (MONDO:0005027), juvenile myoclonic epilepsy (MONDO:0009696), intellectual disability (MONDO:0001071), catecholaminergic polymorphic ventricular tachycardia (MONDO:0017990), sensorineural hearing loss disorder (MONDO:0020678), (MONDO:0011794)

Orphanet (5): Juvenile myoclonic epilepsy (Orphanet:307), Childhood absence epilepsy (Orphanet:64280), Dravet syndrome (Orphanet:33069), Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

98 total (30 of 98 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000153	Abnormality of the mouth
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000466	Limited neck range of motion
HP:0000496	Abnormality of eye movement
HP:0000648	Optic atrophy
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000736	Short attention span
HP:0000739	Anxiety
HP:0000980	Pallor
HP:0000992	Cutaneous photosensitivity
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001300	Parkinsonism
HP:0001327	Photosensitive myoclonic seizure
HP:0001328	Specific learning disability
HP:0001336	Myoclonus
HP:0001763	Pes planus
HP:0002059	Cerebral atrophy
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002104	Apnea
HP:0002121	Generalized non-motor (absence) seizure
HP:0002123	Generalized myoclonic seizure

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003075_70	Cognitive decline rate in late mild cognitive impairment	6.000000e-07
GCST004110_11	Gait speed in old age	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D020190	Myoclonic Epilepsy, Juvenile	C10.228.140.490.375.130.670; C10.228.140.490.493.063.670
C567002	Epilepsy, Childhood Absence, Susceptibility To, 4 (supp.)
C562694	Epilepsy, Idiopathic Generalized (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (13): CHEMBL1907597 (PROTEIN COMPLEX), CHEMBL1962 (SINGLE PROTEIN), CHEMBL2093872 (PROTEIN COMPLEX GROUP), CHEMBL2094121 (PROTEIN COMPLEX), CHEMBL2095172 (PROTEIN COMPLEX), CHEMBL2109243 (PROTEIN COMPLEX GROUP), CHEMBL2109244 (PROTEIN COMPLEX GROUP), CHEMBL2111392 (PROTEIN COMPLEX), CHEMBL3885570 (PROTEIN COMPLEX), CHEMBL4106151 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

60 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 532,203 (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
CHEMBL12	DIAZEPAM	4	92,281
CHEMBL13280	FLUNITRAZEPAM	4	11,549
CHEMBL1522	ESZOPICLONE	4	6,548
CHEMBL407	FLUMAZENIL	4	7,150
CHEMBL646	TRIAZOLAM	4	21,589
CHEMBL661	ALPRAZOLAM	4	130,677
CHEMBL681	ETOMIDATE	4	8,462
CHEMBL911	ZOLPIDEM	4	17,821
CHEMBL1082407	ENZALUTAMIDE	4	9,652
CHEMBL1544	LIOTHYRONINE	4	23,700
CHEMBL1568698	GANAXOLONE	4	1,657
CHEMBL207538	BREXANOLONE	4	1,585
CHEMBL3183409	APALUTAMIDE	4	4,076
CHEMBL452	CLONAZEPAM	4	33,297
CHEMBL15891	LINDANE	4	83,653
CHEMBL451	CHLORDIAZEPOXIDE	4	36,533
CHEMBL526	PROPOFOL	4	28,835
CHEMBL1521	ZALEPLON	4	9,958
CHEMBL1983350	STIRIPENTOL	4	2,890
CHEMBL4105630	ZURANOLONE	4	290
CHEMBL1014	CANDESARTAN CILEXETIL	4
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

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2279020	Efficacy	3	carbamazepine;phenytoin;valproic acid	Epilepsy
rs2290732	Efficacy	3	carbamazepine	Epilepsy

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1157122	GABRA1		0.00	0
rs2279020	GABRA1	3	4.50	1	carbamazepine;phenytoin;valproic acid
rs2290732	GABRA1	3	2.75	1	carbamazepine
rs6883877	GABRA1		0.00	0
rs6892782	GABRA1		0.00	0
rs10068980	GABRA1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — GABA_A receptors

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
CGS8216	Inverse agonist	10.3	pKi
flumazenil	Antagonist	9.1	pKi
ZK93423	Partial agonist	9.0	pKi
triazolam	Positive	9.0	pKd
clonazepam	Positive	8.9	pKi
flunitrazepam	Positive	8.28	pKi
diazepam	Positive	7.79	pKi
zolpidem	Positive	7.68	pKi
alprazolam	Positive	7.43	pEC50
ganaxolone	Potentiation	6.59	pEC50

Binding affinities (BindingDB)

191 measured of 208 human assays (224 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(4-Methoxy-phenyl)-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one (CGS 9895)	KI	0.09 nM
2-Phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one (CGS 8216)	KI	0.11 nM
CGS-20625	KI	0.15 nM
CGS 9896	KI	0.26 nM
8-Bromo-7-oxo-3b,4,5,6-tetrahydro-7H-2,6a,11b-triaza-benzo[g]cyclopenta[e]azulene-3-carboxylic acid tert-butyl ester	KI	0.45 nM
Halcion	KI	0.68 nM
FG 8205	KI	0.68 nM
2-[1-[2-(2-methoxy-3-pyridinyl)-4-pyridinyl]benzimidazol-5-yl]propan-2-ol	IC50	1.2 nM	US-8492408: Benzimidazole derivatives and their use for modulating the GABAA receptor complex
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
CAS_123662	KI	7.1 nM
2-[1-[2-(3-fluoro-4-pyridinyl)-4-pyridinyl]benzimidazol-5-yl]propan-2-ol	IC50	7.5 nM	US-8492408: Benzimidazole derivatives and their use for modulating the GABAA receptor complex
[(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
[(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
NSC_104999	KI	11.2 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
N-((2S)-7-oxabicyclo[2.2.1]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide	KI	16.6 nM	US-11091471: Isoxazolyl ether derivatives as GABAA α5 PAM
6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S,3R,4S)-7-oxabicyclo[2.2.1]heptan-3-yl)pyridazine-3-carboxamide or Enantiomer	KI	18.8 nM	US-11091471: Isoxazolyl ether derivatives as GABAA α5 PAM
6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1R,3S,4R)-7-oxabicyclo[2.2.1]heptan-3-yl)pyridazine-3-carboxamide or Enantiomer	KI	20.7 nM	US-11091471: Isoxazolyl ether derivatives as GABAA α5 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
4-[4-[5-(2-hydroxypropan-2-yl)benzimidazol-1-yl]-2-pyridinyl]pyridine-3-carbonitrile	IC50	26 nM	US-8492408: Benzimidazole derivatives and their use for modulating the GABAA receptor complex
ethyl 12-ethynyl-8-methyl-9-oxo-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(14),3,5,10,12-pentaene-5-carboxylate	KI	28.4 nM
[(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
2-[1-[2-(2-chloro-3-pyridinyl)-4-pyridinyl]benzimidazol-5-yl]propan-2-ol	IC50	38 nM	US-8492408: Benzimidazole derivatives and their use for modulating the GABAA receptor complex
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
(4S)-7-chloro-6-(2,6-difluorophenyl)-N’,N’,4-trimethyl-8-(trifluromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carbohydrazide	KI	99.2 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
(4S)-7-chloro-6-(2,6-difluorophenyl)-N-(2-fluoroethyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide	KI	104 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
[(4S)-7-chloro-6-(3-fluoro-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-ethoxyazetidin-1-yl)methanone	KI	130 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
P4S	KI	151 nM
CAS_4375	KI	160 nM
7,8-dichloro-6-(2,6-difluorophenyl)-2-methyl-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine	KI	164 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
[(4S)-7-chloro-6-(3-fluoro-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone	KI	178 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
2-[(4S)-7-chloro-6-(3-fluoro-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-5-methyl-1,3,4-oxadiazole	KI	179 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
(8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-2-yl)methanol	KI	216 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
azetidin-1-yl-[(4S)-7-chloro-6-(3-fluoro-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]methanone	KI	224 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
5-({12-ethynyl-8-methyl-9-oxo-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(14),3,5,10,12-pentaen-5-yl}carbonyloxy)pentyl 12-ethynyl-8-methyl-9-oxo-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(10),3,5,11,13-pentaene-5-carboxylate	KI	231 nM
3-({12-ethynyl-9-phenyl-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(14),3,5,8,10,12-hexaen-5-yl}carbonyloxy)propyl 12-ethynyl-9-phenyl-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(10),3,5,8,11,13-hexaene-5-carboxylate	KI	236 nM
(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-imidazo[1,2-a][1,4]benzodiazepine	KI	236 nM	US-12365687: Benzodiazepine derivatives as GABA A gamma 1 PAM
CAS_5448	KI	240 nM

ChEMBL bioactivities

2026 potent at pChembl≥5 of 2256 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
10.30	Ki	0.05	nM	CGS-8216
10.22	Ki	0.06	nM	CHEMBL4243764
10.15	Ki	0.07	nM	CHEMBL3144849
10.10	Ki	0.08	nM	CHEMBL3144696
10.00	IC50	0.1	nM	CHEMBL454349
10.00	Ki	0.1	nM	CHEMBL203286
10.00	Kd	0.1	nM	CHEMBL454349
10.00	Ki	0.1	nM	CHEMBL5280240
9.96	Ki	0.11	nM	CHEMBL3144841
9.92	Ki	0.12	nM	CHEMBL487686
9.92	Ki	0.12	nM	CHEMBL488283
9.92	Ki	0.12	nM	CHEMBL469477
9.85	Ki	0.14	nM	CHEMBL487687
9.85	Ki	0.14	nM	CHEMBL1644826
9.85	Ki	0.14	nM	CHEMBL10483
9.82	Ki	0.15	nM	CHEMBL202343
9.80	IC50	0.16	nM	CHEMBL309517
9.80	Ki	0.16	nM	CHEMBL206380
9.77	Ki	0.17	nM	CHEMBL50763
9.74	Ki	0.18	nM	DARIGABAT
9.74	Ki	0.18	nM	CHEMBL323805
9.74	Ki	0.18	nM	CHEMBL3144698
9.72	Ki	0.19	nM	CHEMBL4436326
9.70	Ki	0.2	nM	CHEMBL202952
9.70	Ki	0.2	nM	CHEMBL4060185
9.70	IC50	0.2	nM	CHEMBL4747460
9.70	Ki	0.2	nM	CHEMBL295027
9.66	Ki	0.22	nM	CHEMBL4303594
9.66	Ki	0.22	nM	CHEMBL48403
9.64	Ki	0.23	nM	CHEMBL375742
9.64	Ki	0.23	nM	CHEMBL3144615
9.62	IC50	0.24	nM	CHEMBL79037
9.60	Ki	0.25	nM	CHEMBL427207
9.59	Ki	0.26	nM	MK-0777
9.59	Ki	0.26	nM	CHEMBL3274851
9.57	Ki	0.27	nM	CHEMBL381059
9.57	Ki	0.27	nM	MK-0777
9.55	Ki	0.28	nM	CHEMBL206587
9.54	Ki	0.29	nM	CHEMBL4436326
9.54	Ki	0.29	nM	CHEMBL117931
9.52	Kd	0.3	nM	CGS-9896
9.52	Ki	0.3	nM	CHEMBL290036
9.52	Ki	0.3	nM	CHEMBL49888
9.51	Ki	0.31	nM	CHEMBL203769
9.51	Ki	0.31	nM	CHEMBL203768
9.51	Ki	0.31	nM	CHEMBL115736
9.47	Ki	0.34	nM	CHEMBL4087909
9.46	Ki	0.35	nM	BRETAZENIL
9.44	Ki	0.36	nM	CHEMBL203591

PubChem BioAssay actives

1737 with measured affinity, of 5640 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
8-methoxy-2-phenyl-1H-pyrazolo[4,3-c]quinolin-3-one	72927: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-1-beta-3-gamma-2	ki	0.0001	uM
2-(4-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-3-one	343089: Binding affinity to GABAA alpha-1-beta-2-gamma-2 receptor	kd	0.0001	uM
2-(4-ethynylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-one	72927: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-1-beta-3-gamma-2	ki	0.0001	uM
3,5-difluoro-2-[2-fluoro-5-[3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]phenyl]benzonitrile	260334: Displacement of [3H]Ro 15-1788 from recombinant human GABAA alpha-1 receptor plus beta3gamma2 expressed in L(tk-) cells	ki	0.0001	uM
3-(2,6-difluorophenyl)-5-[4-fluoro-3-(3-fluoro-2-pyridinyl)phenyl]pyridazine	262644: Displacement of [3H]Ro-151788 from recombinant human GABA-Aalpha1 receptor plus beta3gamma2	ki	0.0001	uM
8-ethynyl-2-phenyl-1H-pyrazolo[4,3-c]quinolin-3-one	72927: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-1-beta-3-gamma-2	ki	0.0001	uM
ethyl 6-methoxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate	1932291: Binding affinity to human recombinant GABAA alpha1 receptor assessed as inhibition constant incubated for 1 hrs by liquid scintillation counting analysis	ki	0.0001	uM
2-(4-methylphenyl)-9-(2-thiophen-3-ylethyl)-6H-[1,2,4]triazolo[4,3-c]quinazoline-3,5-dione	552801: Displacement of [3H]flumazenil human recombinant alpha1beta3gamma2 GABA(A) receptor expressed in HEK293 cells after 30 mins by glass fiber filtration 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
2-phenyl-3aH-pyrazolo[4,3-c]quinolin-3-one	72927: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-1-beta-3-gamma-2	ki	0.0001	uM
8-bromo-2-phenyl-1H-pyrazolo[4,3-c]quinolin-3-one	72927: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-1-beta-3-gamma-2	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
2-[2-fluoro-5-[8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]benzonitrile	262219: Displacement of [3H]Ro 15-1788 from human GABA-Aalpha1 receptor plus beta-3-gamma-2 expressed in mouse L(tk-) cells	ki	0.0002	uM
8-chloro-2-phenyl-1H-pyrazolo[4,3-c]quinolin-3-one	72927: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-1-beta-3-gamma-2	ki	0.0002	uM
8-chloro-2-(4-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-3-one	1388015: Displacement of [3H]Ro15-1788 from human GABAA receptor alpha1beta3gamma2 expressed in LTK cells preincubated for 30 secs measured every 15 mins at -60 mV holding potential by two-electrode voltage clamp assay	ki	0.0002	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
2-(4-chlorophenyl)-6,7,8,9-tetrahydro-1H-pyrazolo[4,3-c]quinolin-3-one	221780: In vitro binding affinity against gamma-aminobutyric acid A receptor, alpha 1 expressed in L(tk) cells by displacement of [3H]Ro-151788	ki	0.0002	uM
2-(4-bromophenyl)-1H-pyrazolo[4,3-c]quinolin-3-one	72927: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-1-beta-3-gamma-2	ki	0.0002	uM
7-cyclobutyl-3-(2,6-difluorophenyl)-6-[(2-methyl-1,2,4-triazol-3-yl)methoxy]-[1,2,4]triazolo[4,3-b]pyridazine	1604538: Displacement of [3H]-flumazenil from human GABAA alpha1beta3gamma2 expressed in Ltk cells	ki	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
15-(4-chlorophenyl)-13-(4-methyl-1,3-thiazol-2-yl)-4,11-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2(7),3,5,13-pentaen-12-one	72914: Displacement of [3H]Ro-151788 from human GABA-A receptor alpha-1-beta-3-gamma-2 subunits expressed in L(tk) cells	ki	0.0002	uM
2-(4-chlorophenyl)-8-(pyridin-4-ylmethyl)-1,5a,6,7,9,9a-hexahydropyrazolo[4,3-c][1,6]naphthyridin-3-one	221780: In vitro binding affinity against gamma-aminobutyric acid A receptor, alpha 1 expressed in L(tk) cells by displacement of [3H]Ro-151788	ki	0.0002	uM
3-fluoro-2-[2-fluoro-5-(7-methyl-8-oxoimidazo[1,2-a]pyrazin-3-yl)phenyl]benzonitrile	262295: Displacement of [3H]Ro-151788 from human recombinant GABA-Aalpha1 receptor plus beta3gamma2	ki	0.0002	uM
7-ethyl-4-[3-(4-ethylsulfonyl-2-methoxyphenyl)-4-fluorophenyl]imidazo[4,5-c]pyridazine	1553920: Displacement of [3H]-flumazenil from human GABAA alpha1beta3gamma2 receptor expressed in HEK293 cell membranes measured after 2 hrs by liquid scintillation counting method	ki	0.0002	uM
7-cyclobutyl-6-[(2-methyl-1,2,4-triazol-3-yl)methoxy]-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine	282665: Displacement of [3H]Ro 15-1788 from human recombinant GABAA alpha-1-beta-3-gamma-2 receptor expressed in L(tk-) cells	ki	0.0002	uM
7-methoxy-2-(4-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-3-one	72927: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-1-beta-3-gamma-2	ki	0.0003	uM
tert-butyl (7S)-14-bromo-12-oxo-2,4,11-triazatetracyclo[11.4.0.02,6.07,11]heptadeca-1(17),3,5,13,15-pentaene-5-carboxylate	72927: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-1-beta-3-gamma-2	ki	0.0003	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
2-[5-(7-ethyl-8-oxoimidazo[1,2-a]pyrazin-3-yl)-2-fluorophenyl]-5-fluorobenzonitrile	262295: Displacement of [3H]Ro-151788 from human recombinant GABA-Aalpha1 receptor plus beta3gamma2	ki	0.0003	uM
ethyl 6-benzyl-4-oxo-1H-quinoline-3-carboxylate	262560: Displacement of [3H]Flumazenil from human GABA-Aalpha1 receptor plus beta-2-gamma-2 expressed in HEK293 cells	ki	0.0003	uM
5-fluoro-2-[2-fluoro-5-[3-(trifluoromethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]phenyl]benzonitrile	260334: Displacement of [3H]Ro 15-1788 from recombinant human GABAA alpha-1 receptor plus beta3gamma2 expressed in L(tk-) cells	ki	0.0003	uM
7-bromo-5-(2-fluorophenyl)-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	0.0003	uM
2-(4-methoxyphenyl)-6,7,8,9-tetrahydro-1H-pyrazolo[4,3-c]quinolin-3-one	221780: In vitro binding affinity against gamma-aminobutyric acid A receptor, alpha 1 expressed in L(tk) cells by displacement of [3H]Ro-151788	ki	0.0003	uM
2-(4-chlorophenyl)-3aH-pyrazolo[4,3-c]quinolin-3-one	343089: Binding affinity to GABAA alpha-1-beta-2-gamma-2 receptor	kd	0.0003	uM
2-(4-fluorophenyl)-6,7,8,9-tetrahydro-1H-pyrazolo[4,3-c]quinolin-3-one	221780: In vitro binding affinity against gamma-aminobutyric acid A receptor, alpha 1 expressed in L(tk) cells by displacement of [3H]Ro-151788	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
7-tert-butyl-6-[(2-ethyl-1,2,4-triazol-3-yl)methoxy]-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine	259129: Displacement of [3H]-Ro15-1788 from human recombinant GABAA alpha1 in combination with beta-3-gamma-2 expressed in L(tk-) cells	ki	0.0003	uM
3-(6-bromo-2-pyridinyl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine	261197: Displacement of [3H]Ro 15-1788 from recombinant human GABA-Aalpha1 receptor plus beta-3-gamma-2 expressed in L(tk-) cells	ki	0.0003	uM
7-(trifluoromethyl)-3-[6-(trifluoromethyl)-2-pyridinyl]imidazo[1,2-a]pyrimidine	261197: Displacement of [3H]Ro 15-1788 from recombinant human GABA-Aalpha1 receptor plus beta-3-gamma-2 expressed in L(tk-) cells	ki	0.0003	uM
2-[6-[7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]-2-pyridinyl]benzonitrile	261197: Displacement of [3H]Ro 15-1788 from recombinant human GABA-Aalpha1 receptor plus beta-3-gamma-2 expressed in L(tk-) cells	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
7-tert-butyl-6-[(2-methyl-1,2,4-triazol-3-yl)methoxy]-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine	282665: Displacement of [3H]Ro 15-1788 from human recombinant GABAA alpha-1-beta-3-gamma-2 receptor expressed in L(tk-) cells	ki	0.0004	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
gamma-Aminobutyric Acid	increases reaction, decreases reaction, affects cotreatment, affects reaction, increases response to substance (+2 more)	17
Propofol	decreases reaction, increases activity, increases reaction, affects reaction, affects cotreatment (+1 more)	4
1-(3-chlorophenyl)piperazine	affects cotreatment, affects reaction, increases activity, affects binding, decreases reaction (+2 more)	3
Hexachlorocyclohexane	affects binding, decreases reaction, increases activity, increases reaction	3
Diazepam	affects activity, affects binding, increases activity, increases reaction	3
2,4,2’,4’-tetrachlorobiphenyl	affects binding, increases activity, affects cotreatment, increases reaction, decreases reaction	2
tert-butylbicyclophosphorothionate	affects binding, decreases reaction	2
delta-hexachlorocyclohexane	affects binding, affects cotreatment, increases activity, increases reaction, decreases reaction (+1 more)	2
1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane	increases reaction, affects binding, decreases reaction, affects reaction	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Flunitrazepam	affects reaction, affects binding, increases reaction, increases activity	2
Lead	affects expression, increases expression	2
Pentobarbital	affects binding, decreases reaction, increases activity, increases reaction, affects cotreatment	2
Picrotoxin	affects binding, decreases reaction, increases activity	2
Valproic Acid	decreases methylation, increases expression	2
3,4-Methylenedioxyamphetamine	affects cotreatment, affects reaction, increases activity, affects binding, decreases activity (+1 more)	2
6-methoxyflavone	affects binding, increases activity, increases reaction	1
6-methoxyflavanone	increases activity, increases reaction, affects binding	1
beta-thujone	affects binding, decreases reaction, increases activity	1
1-benzylpiperazine	affects binding, decreases reaction, increases activity	1
bisphenol A	increases methylation	1
carvone	affects binding, increases activity, increases reaction	1
2,5,2’,5’-tetrachlorobiphenyl	affects cotreatment, increases activity, affects binding	1
tetramethylenedisulfotetramine	affects binding, decreases reaction, increases activity, increases reaction	1
trichostatin A	increases expression	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	affects binding, decreases reaction, increases activity	1
menthone	affects binding, increases activity, increases reaction	1
tetrabromobisphenol A	affects binding, affects reaction, increases activity, increases reaction	1

ChEMBL screening assays

842 unique, capped per target: 701 binding, 124 functional, 13 admet, 4 toxicity

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
CHEMBL1687495	Functional	Agonist activity at recombinant GABAA receptor subunit alpha-1 expressed in CHO cells at 3 uM by sensitive fluorometric read-out assay relative to midazolam	Exploring subtype selectivity and metabolic stability of a novel series of ligands for the benzodiazepine binding site of the GABAA receptor. — Bioorg Med Chem Lett
CHEMBL4701824	ADMET	Negative allosteric modulation of recombinant human GABA-A alpha1 expressed in HEK293 cells assessed as reduction in GABA-induced current at 1 uM relative to control	Discovery of ONO-8590580: A novel, potent and selective GABA α negative allosteric modulator for the treatment of cognitive disorders. — Bioorg Med Chem Lett

Cellosaurus cell lines

10 cell lines: 4 cancer cell line, 3 spontaneously immortalized cell line, 2 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B8GL	Abcam HCT 116 GABRA1 KO	Cancer cell line	Male
CVCL_B8W6	Abcam MCF-7 GABRA1 KO	Cancer cell line	Female
CVCL_B9IU	Abcam A-549 GABRA1 KO	Cancer cell line	Male
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
CVCL_D1JK	PrecisION hGABAA alpha1/beta3/gamma2-HEK	Transformed cell line	Female
CVCL_D1SN	Abcam U-87MG GABRA1 KO	Cancer cell line	Male
CVCL_RG01	PFIZi024-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03590197	PHASE4	COMPLETED	Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
NCT03940326	PHASE4	COMPLETED	Levetiracetam Versus Valproate in Idiopathic Generalized Tonic-clonic Seizures
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide