SCN3A

Summary

SCN3A (sodium voltage-gated channel alpha subunit 3, HGNC:10590) is a protein-coding gene on chromosome 2q24.3, encoding Sodium channel protein type 3 subunit alpha (Q9NY46). Pore-forming subunit of Nav1.3, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.

Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6328 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 2,115 total — 9 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 89
• Druggable target: yes — 93 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006922

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10590
Approved symbol	SCN3A
Name	sodium voltage-gated channel alpha subunit 3
Location	2q24.3
Locus type	gene with protein product
Status	Approved
Aliases	Nav1.3
Ensembl gene	ENSG00000153253
Ensembl biotype	protein_coding
OMIM	182391
Entrez	6328

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000283254, ENST00000409101, ENST00000440431, ENST00000453007, ENST00000465043, ENST00000471697, ENST00000638473, ENST00000639244, ENST00000640652, ENST00000658209, ENST00000668657, ENST00000706067

RefSeq mRNA: 3 — MANE Select: NM_006922 NM_001081676, NM_001081677, NM_006922

CCDS: CCDS33312, CCDS46440

Canonical transcript exons

ENST00000283254 — 28 exons

Exon	Start	End
ENSE00001009766	165115455	165115575
ENSE00001009789	165100302	165100424
ENSE00001009801	165162556	165162828
ENSE00001193463	165127631	165128101
ENSE00001193486	165146739	165147029
ENSE00001238274	165113816	165113970
ENSE00001409220	165176131	165176444
ENSE00001415843	165186551	165186747
ENSE00001585797	165203823	165204050
ENSE00001880206	165087526	165091345
ENSE00002440956	165129940	165130296
ENSE00002450011	165164392	165164520
ENSE00002455762	165094374	165094478
ENSE00002478318	165154452	165154658
ENSE00002487187	165168736	165168825
ENSE00002500930	165139476	165139608
ENSE00002513118	165137879	165138117
ENSE00002514373	165112885	165113058
ENSE00002514980	165140651	165140998
ENSE00002517069	165155762	165155903
ENSE00002518476	165163618	165163709
ENSE00002520302	165131244	165131417
ENSE00002520810	165162308	165162371
ENSE00002531807	165170430	165170548
ENSE00003568536	165096467	165096520
ENSE00003615990	165092254	165092524
ENSE00003647141	165095511	165095648
ENSE00003788929	165097252	165097524

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 94.47.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5258 / max 674.6199, expressed in 306 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31652	1.3422	213
31653	0.4570	121
31654	0.4344	108
31651	0.2446	107
31655	0.0477	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	94.47	gold quality
cortical plate	UBERON:0005343	92.49	gold quality
middle temporal gyrus	UBERON:0002771	92.18	gold quality
entorhinal cortex	UBERON:0002728	91.93	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.07	gold quality
orbitofrontal cortex	UBERON:0004167	90.92	gold quality
CA1 field of hippocampus	UBERON:0003881	90.13	gold quality
postcentral gyrus	UBERON:0002581	90.02	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.00	gold quality
cerebellar vermis	UBERON:0004720	89.61	gold quality
superior frontal gyrus	UBERON:0002661	89.52	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	89.36	gold quality
substantia nigra pars compacta	UBERON:0001965	88.35	gold quality
parietal lobe	UBERON:0001872	88.12	gold quality
substantia nigra pars reticulata	UBERON:0001966	87.73	gold quality
ganglionic eminence	UBERON:0004023	85.34	gold quality
medulla oblongata	UBERON:0001896	83.80	gold quality
superior vestibular nucleus	UBERON:0007227	83.55	gold quality
primary visual cortex	UBERON:0002436	83.33	gold quality
temporal lobe	UBERON:0001871	82.16	gold quality
occipital lobe	UBERON:0002021	81.80	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.58	gold quality
hypothalamus	UBERON:0001898	81.49	gold quality
nucleus accumbens	UBERON:0001882	81.09	gold quality
cerebral cortex	UBERON:0000956	81.06	gold quality
frontal cortex	UBERON:0001870	81.03	gold quality
neocortex	UBERON:0001950	80.40	gold quality
telencephalon	UBERON:0001893	79.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	79.83	gold quality
prefrontal cortex	UBERON:0000451	79.71	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	370.01
E-GEOD-93593	yes	13.48
E-CURD-114	yes	11.79
E-ANND-3	yes	6.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IL10, TNF

miRNA regulators (miRDB)

196 targeting SCN3A, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-656-3P	100.00	72.15	2788
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-548AW	99.99	72.57	3559
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197

Literature-anchored findings (GeneRIF, showing 24)

• in autism families, two polymorphic coding variants of SCN3A are described (PMID:12610651)
• Characterization of 5’ untranslated regions SCN3A, and identification of cis-conserved noncoding sequences. (PMID:17544618)
• The association of antiepileptic drugs responsiveness with genetic polymorphisms was investigated and any association with mRNA expression of the neuronal sodium channels was correlated. (PMID:18784617)
• In trigeminal neuralgia (TN) there is a reduction in the expression of Nav1.7 and an increase in the expression of Nav1.3, Nav1.8 expression not significantly different; TN can be, at least in part, a channelopathy. (PMID:19699781)
• Deletions in SCN3A gene is associated with autistic features and developmental delay. (PMID:20346423)
• Upregulation of Nav1.3 protein and a specific cellular distribution of Nav1.3 proteins in focal cortical dysplasia type IIb(FCDIIb) lesion tissue samples suggest that Nav1.3 may be involved in the generation of epileptic activity in FCDIIb. (PMID:22494998)
• This study demonistrated that associated with a duplication of the SCN2A and SCN3A gene cluster on 2q24 in patient with early onset epilepsy. (PMID:23016767)
• Our data from the Hong Kong and Malaysia cohorts showed no significant allele, genotype and haplotype association of polymorphisms in the SCN1A, SCN2A, and SCN3A genes with drug responsiveness in epilepsy. (PMID:23859570)
• the time course of declining expression of the murine embryonic sodium channel Nav 1.3 and the rise in expression of the adult sodium channel Nav 1.1 with susceptibility to epileptic seizures and increased incidence of sudden death (PMID:23965409)
• Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy. (PMID:24157691)
• sodium channel polymorphisms are associated with epilepsy (PMID:24337656)
• sodium channel currents in oocytes expressing either wild-type or mutant (A4V) SOD1 protein (PMID:27072680)
• Data indicate eight new cases with overlapping duplications at 2q24 and SCN3A was not involved in duplication, suggesting that having an extra copy of SCN2A has an effect on epilepsy pathogenesis. (PMID:27153334)
• Novel de novo variant SCN3A-L247P was demonstrated to cause a defect in trafficking, which would be predicted to functionally reduce SCN3A activity. Consistent with the clinical observations, Scn3a+/Hyp mice display increased seizure susceptibility, hypoactivity, and impaired motor learning. (PMID:28235671)
• The findings of this study established SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. (PMID:29466837)
• Study represents the first evidence of the abnormal changes in voltage-gated sodium channels subtypes (including Nav1.3) and CaM/CaMKII pathway in human brain low-grade astrocytoma, providing new potential targets for molecular therapies of this disease. (PMID:29578003)
• SCN3A expression is involved in the prenatal development of human cortical language areas. (PMID:30146301)
• SCN3A is involved in development of the human brain and oral motor development. When SCN3A is mutated, patients present with polymicrogyria and speech deficits. (PMID:30146301)
• Long noncoding RNA HOXA-AS2 regulates the expression of SCN3A by sponging miR-106a in breast cancer. (PMID:30993766)
• SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation. (PMID:32515017)
• Mutations in the sodium channel genes SCN1A, SCN3A, and SCN9A in children with epilepsy with febrile seizures plus(EFS+). (PMID:33895391)
• Association of sodium voltage-gated channel genes polymorphisms with epilepsy risk and prognosis in the Saudi population. (PMID:35801810)
• Targeted blockade of aberrant sodium current in a stem cell-derived neuron model of SCN3A encephalopathy. (PMID:37935051)
• Neurodevelopmental disorder in a patient with HMBS and SCN3A variants-A possibly blended phenotype further delineating autosomal recessive HMBS related disease. (PMID:38568055)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Scn3a	ENSMUSG00000057182
rattus_norvegicus	Scn3a	ENSRNOG00000005007

Paralogs (26): CACNA1G (ENSG00000006283), SCN4A (ENSG00000007314), CACNA1S (ENSG00000081248), CACNA1I (ENSG00000100346), CACNA1F (ENSG00000102001), NALCN (ENSG00000102452), SCN2A (ENSG00000136531), SCN7A (ENSG00000136546), CACNA1A (ENSG00000141837), SCN1A (ENSG00000144285), CACNA1B (ENSG00000148408), CACNA1C (ENSG00000151067), CATSPER3 (ENSG00000152705), CACNA1D (ENSG00000157388), TPCN2 (ENSG00000162341), CATSPER2 (ENSG00000166762), SCN11A (ENSG00000168356), SCN9A (ENSG00000169432), CATSPER1 (ENSG00000175294), SCN5A (ENSG00000183873), SCN10A (ENSG00000185313), TPCN1 (ENSG00000186815), CATSPER4 (ENSG00000188782), CACNA1H (ENSG00000196557), SCN8A (ENSG00000196876), CACNA1E (ENSG00000198216)

Protein

Protein identifiers

Sodium channel protein type 3 subunit alpha — Q9NY46 (reviewed: Q9NY46)

Alternative names: Sodium channel protein brain III subunit alpha, Sodium channel protein type III subunit alpha, Voltage-gated sodium channel subtype III, Voltage-gated sodium channel subunit alpha Nav1.3

All UniProt accessions (9): Q9NY46, A0A1W2PQ58, A0A1W2PRD1, A0A1W2PSB2, A0A590UJH3, A0A590UJW3, A0A994J5P2, C9JBM7, E7EUE6

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of Nav1.3, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na+ ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues. In some secretory cell types, it also participates in cell excitability through membrane depolarization and regulates cells responsiveness to stimuli triggering secretion. For instance, it controls the release of serotonin/5-hydroxytryptamine by enterochromaffin cells and is required for both glucagon- and glucose-induced insulin secretion in pancreatic endocrine cells.

Subunit / interactions. Heterooligomer of an alpha subunit, SCN3A, and 1 to 3 regulatory beta subunits including SCN1B and SCN2B; disulfide-linked with some beta subunits like SCN2B. Interacts with NEDD4L; could regulate expression of SCN3A at the plasma membrane through ubiquitination-regulated endocytosis. Interacts with the conotoxin GVIIJ.

Subcellular location. Cell membrane. Basal cell membrane.

Tissue specificity. Expressed in enterochromaffin cells in both colon and small bowel (at protein level).

Post-translational modifications. May be ubiquitinated by NEDD4L; which would promote its endocytosis. Phosphorylation at Ser-1501 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents.

Disease relevance. Epilepsy, familial focal, with variable foci 4 (FFEVF4) [MIM:617935] An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. Seizure types commonly include temporal lobe epilepsy, frontal lobe epilepsy, and nocturnal frontal lobe epilepsy. Some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. A subset of patients have structural brain abnormalities. Penetrance of the disorder is incomplete. FFEVF4 is characterized by onset of focal seizures in the first years of life. The disease is caused by variants affecting the gene represented in this entry. Developmental and epileptic encephalopathy 62 (DEE62) [MIM:617938] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE62 is characterized by onset of seizures in the first year of life. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The sequence contains 4 internal repeats, each with 5 hydrophobic segments (S1, S2, S3, S5, S6) and one positively charged segment (S4). Segments S4 are probably the voltage-sensors and are characterized by a series of positively charged amino acids at every third position.

Similarity. Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.3/SCN3A subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NY46-1	1, 6A-12+12b	yes
Q9NY46-2	2, 6A-12
Q9NY46-3	3, 6N-12+12b
Q9NY46-4	4, 6N-12

RefSeq proteins (3): NP_001075145, NP_001075146, NP_008853* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001696	Na_channel_asu	Family
IPR005821	Ion_trans_dom	Domain
IPR010526	Na_trans_assoc_dom	Domain
IPR024583	Na_trans_cytopl	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR043203	VGCC_Ca_Na	Family
IPR044564	Na_chnl_inactivation_gate	Domain
IPR058542	IQ_SCN5A_C	Domain

Pfam: PF00520, PF06512, PF11933, PF24609

Catalyzed reactions (Rhea), 1 shown:

• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (215 total): helix 56, topological domain 29, transmembrane region 24, turn 17, sequence variant 16, sequence conflict 16, strand 15, glycosylation site 8, region of interest 6, compositionally biased region 6, disulfide bond 5, intramembrane region 4, repeat 4, modified residue 4, splice variant 2, chain 1, mutagenesis site 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7W77	ELECTRON MICROSCOPY	3.3
7W7F	ELECTRON MICROSCOPY	3.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NY46-F1	68.76	0.17

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 484, 485, 486, 1501

Disulfide bonds (5): 911, 911, 913–919, 951–960, 1364–1384

Glycosylation sites (8): 211, 290, 296, 302, 307, 339, 1366, 1380

Mutagenesis-validated functional residues (1):

Position	Phenotype
1970	abolishes interaction with nedd4l.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-445095	Interaction between L1 and Ankyrins
R-HSA-5576892	Phase 0 - rapid depolarisation
R-HSA-9717207	Sensory perception of sweet, bitter, and umami (glutamate) taste
R-HSA-1266738	Developmental Biology
R-HSA-373760	L1CAM interactions
R-HSA-397014	Muscle contraction
R-HSA-422475	Axon guidance
R-HSA-5576891	Cardiac conduction
R-HSA-9675108	Nervous system development
R-HSA-9709957	Sensory Perception
R-HSA-9717189	Sensory perception of taste

MSigDB gene sets: 0 (showing top):

GO Biological Process (13): sodium ion transport (GO:0006814), sodium ion transmembrane transport (GO:0035725), behavioral response to pain (GO:0048266), cardiac muscle cell action potential involved in contraction (GO:0086002), membrane depolarization during action potential (GO:0086010), action potential (GO:0001508), regulation of heart rate (GO:0002027), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), cardiac muscle cell action potential (GO:0086001), regulation of muscle system process (GO:0090257), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (4): voltage-gated sodium channel activity (GO:0005248), monoatomic ion channel activity (GO:0005216), monoatomic cation channel activity (GO:0005261), sodium channel activity (GO:0005272)

GO Cellular Component (6): voltage-gated sodium channel complex (GO:0001518), plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), sarcoplasm (GO:0016528), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
L1CAM interactions	1
Cardiac conduction	1
Sensory perception of taste	1
Axon guidance	1
Nervous system development	1
Muscle contraction	1
Developmental Biology	1
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
action potential	2
transport	2
metal ion transport	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
behavior	1
response to pain	1
cardiac muscle cell action potential	1
cardiac muscle cell contraction	1
membrane depolarization	1
regulation of membrane potential	1
regulation of heart contraction	1
regulation of biological quality	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
muscle system process	1
regulation of system process	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
sodium channel activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic ion channel activity	1
monoatomic cation transmembrane transporter activity	1
monoatomic cation channel activity	1
sodium ion transmembrane transporter activity	1
sodium channel complex	1
plasma membrane protein complex	1
membrane	1
cell periphery	1
basal part of cell	1
plasma membrane region	1
cytoplasm	1
cellular anatomical structure	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

1426 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCN3A	SCN1B	Q07699	889
SCN3A	NAV1	Q8NEY1	814
SCN3A	SCNM1	Q9BWG6	669
SCN3A	KCNC2	Q96PR1	643
SCN3A	KCNC3	Q14003	619
SCN3A	SCN2B	O60939	601
SCN3A	SCN3B	Q9NY72	599
SCN3A	SCN4B	Q8IWT1	586
SCN3A	KCNA7	Q96RP8	573
SCN3A	KCNQ2	O43526	564
SCN3A	CNTN1	Q12860	518
SCN3A	KCNA2	P16389	503
SCN3A	GJA1	P17302	497
SCN3A	TRPV1	Q8NER1	491
SCN3A	MYH10	P35580	489

IntAct

11 interactions, top by confidence:

A	B	Type	Score
SCN3A	ATP5PD	psi-mi:“MI:0915”(physical association)	0.400
SCN3A	PDIA3	psi-mi:“MI:0915”(physical association)	0.400
SCN2A	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	CACNB4	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
SCN2A	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
PTBP3		psi-mi:“MI:0914”(association)	0.350
CEP83	NEDD1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (17): SCN3A (Proximity Label-MS), SCN3A (Affinity Capture-MS), SCN3A (Affinity Capture-MS), SCN3A (Reconstituted Complex), SCN3A (Affinity Capture-Western), SCN3A (Two-hybrid), SCN3A (Two-hybrid), SCN3A (Two-hybrid), SCN3A (Proximity Label-MS), SCN3A (Proximity Label-MS), SCN3A (Affinity Capture-MS), SCN3A (Cross-Linking-MS (XL-MS)), SCN3A (Affinity Capture-MS), SCN3A (Affinity Capture-Western), PSAT1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A2APX8, A2ASI5, B1AWN6, C9D7C2, D0E0C2, O08562, O35505, O46669, O73700, O88420, O88457, P02719, P04774, P04775, P08104, P0DMA5, P15381, P15389, P15390, P22002, P27732, P35498, P35499, P35500, Q01815, Q07652, Q13936, Q14524, Q15858, Q20JQ7, Q28371, Q28644, Q2XVR3, Q2XVR4, Q2XVR5, Q2XVR6, Q2XVR7, Q62205, Q62968, Q6QIY3

Diamond homologs: A2APX8, A2ASI5, B1AWN6, B1AYL1, D0E0C2, F1LQQ7, O00555, O08562, O46669, O73705, O73706, O73707, O88420, O88457, P02719, P04774, P04775, P08104, P0DMA5, P15389, P15390, P27884, P35498, P35499, P35500, P54282, P56699, P97445, Q01118, Q02789, Q05973, Q14524, Q15858, Q15878, Q20JQ7, Q28371, Q28644, Q2XVR3, Q2XVR4, Q2XVR5

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
SCN3A	“up-regulates quantity”	sodium(1+)	relocalization
FGF13	“down-regulates activity”	SCN3A	binding
FGF12	“down-regulates activity”	SCN3A	binding
FGF14	“down-regulates activity”	SCN3A	binding
FGF11	“down-regulates activity”	SCN3A	binding
SCN3A	up-regulates	Action_potential
“CoREST-HDAC complex”	“down-regulates quantity by repression”	SCN3A	“transcriptional regulation”
NEDD4L	“down-regulates quantity by destabilization”	SCN3A	ubiquitination
TNF	“up-regulates quantity by expression”	SCN3A	“transcriptional regulation”
TNF	“up-regulates activity”	SCN3A
IL10	“down-regulates quantity by repression”	SCN3A	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

2115 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	27
Uncertain significance	1180
Likely benign	711
Benign	76

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1365761	NM_006922.4(SCN3A):c.585_586del (p.Phe195fs)	Pathogenic
1454182	NC_000002.11:g.(?165946660)(166153665_?)del	Pathogenic
1802268	NM_006922.4(SCN3A):c.2017G>T (p.Glu673Ter)	Pathogenic
208754	NM_006922.4(SCN3A):c.1318C>T (p.Gln440Ter)	Pathogenic
373960	NM_006922.4(SCN3A):c.2624T>C (p.Ile875Thr)	Pathogenic
4819726	NM_006922.4(SCN3A):c.3393+2T>G	Pathogenic
522566	NM_006922.3(SCN3A):c.742T>C (p.Ser248Pro)	Pathogenic
814340	GRCh37/hg19 2q24.3(chr2:166055469-166219950)x1	Pathogenic
872398	NM_006922.4(SCN3A):c.740T>C (p.Leu247Pro)	Pathogenic
1066525	NM_006922.4(SCN3A):c.4387T>C (p.Phe1463Leu)	Likely pathogenic
1304186	NM_006922.4(SCN3A):c.1859G>A (p.Arg620Gln)	Likely pathogenic
1320056	NM_006922.4(SCN3A):c.5621T>G (p.Met1874Arg)	Likely pathogenic
1329932	NM_006922.4(SCN3A):c.2564T>C (p.Leu855Pro)	Likely pathogenic
1329933	NM_006922.4(SCN3A):c.2653C>T (p.Leu885Phe)	Likely pathogenic
1329935	NM_006922.4(SCN3A):c.4518del (p.Lys1506fs)	Likely pathogenic
1329936	NM_006922.4(SCN3A):c.4937T>C (p.Phe1646Ser)	Likely pathogenic
1329937	NM_006922.4(SCN3A):c.5006A>G (p.Tyr1669Cys)	Likely pathogenic
1331640	NM_006922.4(SCN3A):c.4448T>G (p.Ile1483Ser)	Likely pathogenic
1348783	NM_006922.4(SCN3A):c.2681T>C (p.Phe894Ser)	Likely pathogenic
2790904	NM_006922.4(SCN3A):c.4403T>C (p.Ile1468Thr)	Likely pathogenic
2849299	NM_006922.4(SCN3A):c.713G>C (p.Gly238Ala)	Likely pathogenic
3063575	NM_006922.4(SCN3A):c.694+2T>G	Likely pathogenic
3367041	NM_006922.4(SCN3A):c.4431+1A>G	Likely pathogenic
3384046	NM_006922.4(SCN3A):c.3723_3727dup (p.Ala1243fs)	Likely pathogenic
3571492	Single allele	Likely pathogenic
4073635	NM_006922.4(SCN3A):c.4853C>T (p.Thr1618Ile)	Likely pathogenic
4073661	NM_006922.4(SCN3A):c.602C>A (p.Ala201Glu)	Likely pathogenic
4293969	NM_006922.4(SCN3A):c.19del (p.Val7fs)	Likely pathogenic
431726	NM_006922.4(SCN3A):c.626T>C (p.Leu209Pro)	Likely pathogenic
4745724	NM_006922.4(SCN3A):c.4456A>G (p.Thr1486Ala)	Likely pathogenic

SpliceAI

4003 predictions. Top by Δscore:

Variant	Effect	Δscore
2:165092250:TTACC:T	donor_loss	1.0000
2:165092251:TA:T	donor_loss	1.0000
2:165092252:A:AC	donor_gain	1.0000
2:165092253:C:CA	donor_loss	1.0000
2:165092253:C:CC	donor_gain	1.0000
2:165092253:CCTA:C	donor_gain	1.0000
2:165092272:C:CT	donor_gain	1.0000
2:165092520:TTGTT:T	acceptor_gain	1.0000
2:165092521:TGTT:T	acceptor_gain	1.0000
2:165092522:GTT:G	acceptor_gain	1.0000
2:165092523:TT:T	acceptor_gain	1.0000
2:165092525:C:CC	acceptor_gain	1.0000
2:165092525:CTAGA:C	acceptor_loss	1.0000
2:165092532:G:C	acceptor_gain	1.0000
2:165092532:G:GC	acceptor_gain	1.0000
2:165094372:A:AC	donor_gain	1.0000
2:165094372:ACTG:A	donor_gain	1.0000
2:165094373:C:CC	donor_gain	1.0000
2:165094373:CTG:C	donor_gain	1.0000
2:165094373:CTGC:C	donor_gain	1.0000
2:165094475:CAAAG:C	acceptor_gain	1.0000
2:165094476:A:T	acceptor_gain	1.0000
2:165094479:G:GC	acceptor_gain	1.0000
2:165095509:A:AC	donor_gain	1.0000
2:165095509:ATCTT:A	donor_gain	1.0000
2:165095579:C:CT	acceptor_gain	1.0000
2:165095579:C:T	acceptor_gain	1.0000
2:165095647:ACCTA:A	acceptor_loss	1.0000
2:165095648:CCTA:C	acceptor_loss	1.0000
2:165095649:CTAA:C	acceptor_loss	1.0000

AlphaMissense

13394 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:165090606:A:C	C1849W	1.000
2:165090637:A:G	L1839P	1.000
2:165090764:A:G	W1797R	1.000
2:165090764:A:T	W1797R	1.000
2:165090861:G:C	N1764K	1.000
2:165090861:G:T	N1764K	1.000
2:165091020:C:A	W1711C	1.000
2:165091020:C:G	W1711C	1.000
2:165091022:A:G	W1711R	1.000
2:165091022:A:T	W1711R	1.000
2:165091279:A:G	L1625P	1.000
2:165095548:C:T	G1465D	1.000
2:165095549:C:G	G1465R	1.000
2:165095557:A:G	L1462P	1.000
2:165095557:A:T	L1462Q	1.000
2:165095559:A:C	N1461K	1.000
2:165095559:A:T	N1461K	1.000
2:165095563:A:G	L1460P	1.000
2:165095578:C:T	G1455E	1.000
2:165095579:C:A	G1455W	1.000
2:165095579:C:G	G1455R	1.000
2:165095579:C:T	G1455R	1.000
2:165095589:A:C	F1451L	1.000
2:165095589:A:T	F1451L	1.000
2:165095591:A:G	F1451L	1.000
2:165096503:C:A	W1419C	1.000
2:165096503:C:G	W1419C	1.000
2:165096505:A:G	W1419R	1.000
2:165096505:A:T	W1419R	1.000
2:165096508:C:G	G1418R	1.000

dbSNP variants (sampled 300 via entrez): RS1000002075 (2:165122054 A>G), RS1000009829 (2:165092679 TA>T,TAA), RS1000014557 (2:165202787 T>C), RS1000050185 (2:165141522 T>A), RS1000103012 (2:165177296 T>C), RS1000109028 (2:165148675 C>G), RS1000115824 (2:165120204 A>G,T), RS1000122007 (2:165129362 T>C,G), RS1000142936 (2:165141232 A>G), RS1000143944 (2:165091435 C>G), RS1000163684 (2:165196158 A>C), RS1000188192 (2:165167683 T>C), RS1000194453 (2:165175805 C>T), RS1000197660 (2:165162486 C>T), RS1000200034 (2:165195716 T>G)

Disease associations

OMIM: gene MIM:182391 | disease phenotypes: MIM:617935, MIM:617938, MIM:308350, MIM:604827, MIM:604364, MIM:607745, MIM:613721

GenCC curated gene-disease

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Definitive	Autosomal dominant
epilepsy, familial focal, with variable foci 4	Strong	Autosomal dominant
developmental and epileptic encephalopathy, 62	Strong	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
genetic developmental and epileptic encephalopathy	Definitive	AD

Mondo (14): epilepsy, familial focal, with variable foci 4 (MONDO:0054776), developmental and epileptic encephalopathy, 62 (MONDO:0033371), genetic developmental and epileptic encephalopathy (MONDO:0100062), epilepsy, idiopathic generalized, susceptibility to, 7 (MONDO:0011491), epilepsy, familial focal, with variable foci 1 (MONDO:0024556), developmental and epileptic encephalopathy (MONDO:0100620), seizures, benign familial infantile, 3 (MONDO:0011904), developmental and epileptic encephalopathy, 11 (MONDO:0013388), developmental and epileptic encephalopathy, 1 (MONDO:0010632), epilepsy (MONDO:0005027), polymicrogyria (MONDO:0000087), bilateral perisylvian polymicrogyria (MONDO:0020340), neurodevelopmental disorder (MONDO:0700092), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (6): Juvenile myoclonic epilepsy (Orphanet:307), Self-limited neonatal-infantile epilepsy (Orphanet:140927), Early infantile developmental and epileptic encephalopathy (Orphanet:1934), Self-limited infantile epilepsy (Orphanet:306), Polymicrogyria (Orphanet:35981), Bilateral perisylvian polymicrogyria (Orphanet:98889)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000274	Small face
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:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
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:0001336	Myoclonus

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST004902_17	Parkinson’s disease	3.000000e-08
GCST005051_6	Obstructive sleep apnea trait (apnea hypopnea index)	6.000000e-07
GCST005051_7	Obstructive sleep apnea trait (apnea hypopnea index)	6.000000e-07
GCST005950_14	Body mass index x sex x age interaction (4df test)	4.000000e-07
GCST005951_55	Body mass index	3.000000e-06
GCST005952_7	Body mass index (age>50)	4.000000e-09
GCST005957_2	Waist-to-hip ratio adjusted for BMI (age <50)	1.000000e-16
GCST005958_3	Waist-to-hip ratio adjusted for BMI (age >50)	1.000000e-16
GCST005962_14	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-29
GCST007343_2	Epilepsy	2.000000e-13
GCST007352_1	Focal epilepsy	7.000000e-09
GCST007353_3	Generalized epilepsy	5.000000e-08
GCST009391_1704	Metabolite levels	3.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007817	sleep apnea measurement
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0010340	cholesteryl ester 14:0 measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D065886	Neurodevelopmental Disorders	F03.625
D065706	Polymicrogyria	C10.500.507.500.500; C16.131.666.507.500.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2096682 (PROTEIN FAMILY), CHEMBL2331043 (PROTEIN FAMILY), CHEMBL5163 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

93 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 507,182 (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
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL1086	DIBUCAINE	4	17,231
CHEMBL1093	ARTICAINE	4	6,583
CHEMBL1098	BUPIVACAINE	4	37,899
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL1108	DROPERIDOL	4	16,888
CHEMBL1123	DICYCLOMINE	4	8,691
CHEMBL117785	TETRABENAZINE	4	9,645
CHEMBL1193	PHENIRAMINE	4	11,218
CHEMBL1194	PRILOCAINE	4	15,137
CHEMBL1195	PROPOXYCAINE	4	5,653
CHEMBL1196	PROPARACAINE	4	12,973
CHEMBL1197	HEXYLCAINE	4	4,372
CHEMBL1198	PRAMOXINE	4	10,295
CHEMBL1200	BENOXINATE	4	6,712
CHEMBL1294	QUINIDINE	4	71,943
CHEMBL1480	FELODIPINE	4	30,761
CHEMBL16	PHENYTOIN	4	53,375
CHEMBL170	QUININE	4	108,216
CHEMBL1726	NISOLDIPINE	4	18,921
CHEMBL193	NIFEDIPINE	4
CHEMBL2	PRAZOSIN	4
CHEMBL23	DILTIAZEM	4
CHEMBL24072	PRENYLAMINE	4
CHEMBL370805	COCAINE	4
CHEMBL422	TRIFLUOPERAZINE	4
CHEMBL43064	CINNARIZINE	4
CHEMBL479	THIORIDAZINE	4
CHEMBL492	ETIDOCAINE	4
CHEMBL505	CHLORPHENIRAMINE	4

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: vgic — Voltage-gated sodium channels (Na_V)

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
PF‐06526290	Inhibition	8.96	pEC50
tetrodotoxin	Pore blocker	8.4	pIC50
ICA-121431	Channel blocker	7.72	pIC50
AFT-II	Slows inactivation	6.3	pEC50
ATX-II	Slows inactivation	6.1	pEC50
GNE-616	Inhibition	6.0	pKd
Bc-III	Slows inactivation	5.8	pEC50
cannabidiol	Channel blocker	5.48	pIC50
lacosamide	Antagonist	3.4	pIC50

Binding affinities (BindingDB)

576 measured of 580 human assays (580 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-cyclopropyl-4-[(3R)-1-[(3,5-dichlorophenyl)methyl]piperidin-3-yl]oxy-2-fluoro-N-methylsulfonylbenzamide	IC50	0.3 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[[1-[(3,5-dichlorophenyl)-phenylmethyl]piperidin-4-yl]methoxy]-2-fluorobenzamide	IC50	0.8 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[[3-chloro-5-(trifluoromethoxy)phenyl]methyl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	1.3 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(3,5-dichlorophenyl)-phenylmethyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.5 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(2S)-2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.6 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl]piperidin-4-yl]methoxy]-N-ethylsulfonyl-2-fluorobenzamide	IC50	1.6 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichloro-2-fluorophenyl)ethyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.6 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	1.6 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[(2-chlorophenyl)methyl]piperidin-3-yl]oxy-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluorobenzamide	IC50	1.7 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[(3R)-1-[(2,4-dichlorophenyl)methyl]piperidin-3-yl]oxy-2-fluoro-N-methylsulfonylbenzamide	IC50	1.7 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1R)-1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl]piperidin-4-yl]methoxy]-N-ethylsulfonyl-2-fluorobenzamide	IC50	1.7 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[2-(3,5-dichlorophenyl)propan-2-yl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.7 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-methylpiperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.7 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.8 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-2-fluoro-4-[(3R)-1-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]piperidin-3-yl]oxy-N-methylsulfonylbenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[(3R)-1-[(1S)-1-(3,5-dichlorophenyl)ethyl]piperidin-3-yl]oxy-2-fluoro-N-methylsulfonylbenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[[3-chloro-5-(trifluoromethoxy)phenyl]methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[2-(3,5-dichlorophenyl)propan-2-yl]piperidin-4-yl]methoxy]-N-ethylsulfonyl-2-fluorobenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
N-(azetidin-1-ylsulfonyl)-4-[(3R,6R)-1-[(2-chloro-4-fluorophenyl)methyl]-6-methylpiperidin-3-yl]oxy-5-cyclopropyl-2-fluorobenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R,6R)-1-[(2-chloro-4-fluorophenyl)methyl]-6-methylpiperidin-3-yl]oxy-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluorobenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[1-(3,5-dichlorophenyl)propyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	2 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[bis(3-chlorophenyl)methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[bis(2-chlorophenyl)methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[(3R)-1-(3,5-dichlorophenyl)piperidin-3-yl]oxy-2-fluorobenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[[2,5-bis(trifluoromethyl)phenyl]methyl]-4-methylpiperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[[3-chloro-5-(trifluoromethyl)phenyl]methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[bis(4-chlorophenyl)methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluorobenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[(3R)-1-[(2,4-dimethylphenyl)methyl]piperidin-3-yl]oxy-2-fluoro-N-methylsulfonylbenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[5-chloro-4-(trifluoromethyl)-2-pyridinyl]-4-methylpiperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1S)-1-(2,4-dichlorophenyl)ethyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	2.2 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[[1-[(3,5-dichlorophenyl)methyl]piperidin-4-yl]methoxy]-2-fluorobenzamide	IC50	2.2 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[(2-chloro-4-fluorophenyl)methyl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.2 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[(1R,5S)-3-[3-chloro-5-(trifluoromethoxy)phenoxy]-8-azabicyclo[3.2.1]octan-8-yl]methyl]-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluorobenzamide	IC50	2.2 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[4-(3,5-dichlorophenyl)sulfanylpiperidin-1-yl]methyl]-2-fluorobenzamide	IC50	2.2 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)-2-methoxyethyl]piperidin-4-yl]methoxy]-2-fluorobenzamide	IC50	2.3 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[(1S)-1-(2-chloro-4-fluorophenyl)ethyl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.3 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[(1S)-1-(5-chloro-6-cyclopropyl-2-pyridinyl)ethyl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.3 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[2-(3-chlorophenyl)propan-2-yl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluorobenzamide	IC50	2.3 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[(3R)-1-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]piperidin-3-yl]oxybenzamide	IC50	2.4 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[[5-chloro-2-(trifluoromethyl)phenyl]methyl]-4-methylpiperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.4 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1R)-1-(3,5-dichlorophenyl)propyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	2.4 nM	US-9694002: Substituted benzamides and methods of use thereof
N-(azetidin-1-ylsulfonyl)-4-[(3R,6S)-1-[(2-chloro-4-fluorophenyl)methyl]-6-methylpiperidin-3-yl]oxy-5-cyclopropyl-2-fluorobenzamide	IC50	2.4 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(3,5-dichlorophenyl)-phenylmethyl]-3-methylazetidin-3-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	2.4 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[[1-[1-(3,5-dichlorophenyl)ethyl]piperidin-4-yl]methoxy]-2-fluorobenzamide	IC50	2.5 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1R)-1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	2.5 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(2,4-dichlorophenyl)methyl]piperidin-4-yl]methoxy]-N-ethylsulfonyl-2-fluorobenzamide	IC50	2.5 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[[1-[(3,5-dichlorophenyl)-phenylmethyl]-3-methylazetidin-3-yl]methoxy]-2-fluorobenzamide	IC50	2.5 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[(2-chloro-4-methylphenyl)methyl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.5 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[(3R)-1-[(3,5-dichlorophenyl)methyl]piperidin-3-yl]oxy-2-fluorobenzamide	IC50	2.6 nM	US-9694002: Substituted benzamides and methods of use thereof

ChEMBL bioactivities

171 potent at pChembl≥5 of 285 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	TETRODOTOXIN
8.40	IC50	4	nM	TETRODOTOXIN
8.28	IC50	5.3	nM	TETRODOTOXIN
7.96	IC50	11	nM	CHEMBL4276884
7.89	IC50	13	nM	CHEMBL4293085
7.89	IC50	13	nM	SAXITOXIN
7.82	IC50	15.02	nM	BREVETOXIN B
7.77	IC50	17	nM	CHEMBL3617053
7.70	IC50	20	nM	CHEMBL4284819
7.70	IC50	20	nM	CHEMBL5630885
7.69	IC50	20.3	nM	CHEMBL3416886
7.66	IC50	22	nM	CHEMBL4276813
7.60	IC50	25	nM	CHEMBL3318132
7.52	IC50	30	nM	CHEMBL2324354
7.35	IC50	45	nM	CHEMBL4278251
7.27	IC50	54	nM	PIMOZIDE
7.25	IC50	56	nM	CHEMBL5630002
6.96	Kd	110	nM	CHEMBL4471012
6.96	IC50	110	nM	CHEMBL4436427
6.91	IC50	124	nM	CHEMBL4283626
6.83	IC50	147	nM	CHEMBL4290011
6.81	IC50	155	nM	CHEMBL4293390
6.80	IC50	160	nM	CHEMBL4288933
6.75	Kd	180	nM	CHEMBL4444707
6.71	IC50	197	nM	CHEMBL4292031
6.70	IC50	200	nM	CHEMBL4517378
6.68	IC50	210	nM	CHEMBL4588728
6.62	IC50	237	nM	CHEMBL4295123
6.62	IC50	240	nM	CHEMBL5630223
6.58	IC50	260	nM	CHEMBL4469517
6.57	IC50	270	nM	LOPERAMIDE
6.55	IC50	280	nM	FLUPERAMIDE
6.54	IC50	292	nM	CHEMBL2324411
6.53	IC50	296	nM	CHEMBL4290885
6.52	IC50	300	nM	PRENYLAMINE
6.52	IC50	300	nM	CHEMBL1813048
6.50	IC50	320	nM	CHEMBL1426769
6.48	IC50	330	nM	CHEMBL5624797
6.43	IC50	374	nM	CHEMBL4284536
6.42	IC50	380	nM	CHEMBL5625104
6.42	IC50	380	nM	CHEMBL5630705
6.40	IC50	400	nM	TETRACAINE
6.36	IC50	440	nM	CHEMBL5630319
6.36	IC50	440	nM	CINNARIZINE
6.30	IC50	500	nM	CHEMBL52359
6.28	IC50	522	nM	CHEMBL4283701
6.22	IC50	600	nM	FLUNARIZINE
6.22	IC50	600	nM	SPIPERONE
6.22	IC50	600	nM	DILAZEP
6.13	IC50	740	nM	TETRACAINE

PubChem BioAssay actives

179 with measured affinity, of 751 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.17,11.01,6]tetradec-3-ene-5,9,12,13,14-pentol	2133187: Inhibition of human Nav1.3 expressed in CHO cells under inactivated state by automated patch clamp electrophysiology analysis	ic50	0.0010	uM
N-[[3-chloro-4-(trifluoromethoxy)phenyl]methyl]-3-fluoro-4-(1,3-thiazol-2-ylsulfamoyl)benzamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.0110	uM
N-[[3-chloro-4-(trifluoromethoxy)phenyl]methyl]-3-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)benzamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.0130	uM
[(3aS,4R,10aS)-2,6-diamino-10,10-dihydroxy-3a,4,8,9-tetrahydro-1H-pyrrolo[1,2-c]purin-4-yl]methyl carbamate	1525390: Inhibition of human Nav1.3 expressed in HEK293 cells by electrophysiology assay	ic50	0.0130	uM
2-[[(1R,3S,5R,7S,9R,11S,12S,14R,16R,18S,20R,21Z,24S,26R,28S,30R,31R,33S,35R,37S,42R,44S,46R,48S)-12-hydroxy-1,3,11,24,31,41,44-heptamethyl-39-oxo-2,6,10,15,19,25,29,34,38,43,47-undecaoxaundecacyclo[26.22.0.03,26.05,24.07,20.09,18.011,16.030,48.033,46.035,44.037,42]pentaconta-21,40-dien-14-yl]methyl]prop-2-enal	254847: Inhibitory concentration against synaptosome using [3H]PbTx-3	ic50	0.0150	uM
2,2-diphenyl-N-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]acetamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.0170	uM
2-(3,4-difluorophenyl)-N-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]cyclopropane-1-carboxamide	2133187: Inhibition of human Nav1.3 expressed in CHO cells under inactivated state by automated patch clamp electrophysiology analysis	ic50	0.0200	uM
N-[[3-chloro-4-(trifluoromethoxy)phenyl]methyl]-4-(1,3-thiazol-2-ylsulfamoyl)benzamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.0200	uM
(3S)-3-amino-4-[[(1R,4S,10S,13S,16S,19S,22S,25R,30R,33S,36S,39S,42S,45S,48S,51R,54S,57S,60S,63S,69S,72R,77R,80S,86S,89S,92S,95S)-30-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]carbamoyl]-22,36,95-tris(4-aminobutyl)-16,60-bis(2-amino-2-oxoethyl)-86-benzyl-4-[(2S)-butan-2-yl]-45,69,92-tris(3-carbamimidamidopropyl)-13,19-bis(carboxymethyl)-42-[(1R)-1-hydroxyethyl]-48-(hydroxymethyl)-39-(1H-imidazol-4-ylmethyl)-33-(1H-indol-3-ylmethyl)-57,80-bis(2-methylpropyl)-89-(2-methylsulfanylethyl)-2,3a,5,11,14,17,20,23,32,35,38,41,44,47,50,53,56,59,62,68,71,78,81,84,87,90,93,96-octacosaoxo-54-propan-2-yl-a,27,28,74,75,99-hexathia-2a,3,6,12,15,18,21,24,31,34,37,40,43,46,49,52,55,58,61,67,70,79,82,85,88,91,94,97-octacosazapentacyclo[49.46.4.225,72.06,10.063,67]trihectan-77-yl]amino]-4-oxobutanoic acid	1200072: Inhibition of human NaV1.3 at -140 mV holding potential by whole-cell patch clamp assay	ic50	0.0203	uM
4-[[3-chloro-4-(trifluoromethoxy)phenyl]methoxy]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.0220	uM
(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(1R,4S,7S,13S,16R,21R,24S,27S,30S,33S,36S,39S,42R,45S,48S,51S,54S,57S,60R,65R,68S,71S,74S)-27,57-bis(4-aminobutyl)-21-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-24-(3-amino-3-oxopropyl)-54,74-bis(3-carbamimidamidopropyl)-13,51-bis(2-carboxyethyl)-45-(carboxymethyl)-39-[(1R)-1-hydroxyethyl]-48-(hydroxymethyl)-30,36,68-tris(1H-indol-3-ylmethyl)-71-(2-methylpropyl)-7,33-bis(2-methylsulfanylethyl)-3,6,9,12,15,22,25,28,31,34,37,40,43,46,49,52,55,58,67,70,73,76,81-tricosaoxo-4-propan-2-yl-18,19,62,63,78,79-hexathia-2,5,8,11,14,23,26,29,32,35,38,41,44,47,50,53,56,59,66,69,72,75,82-tricosazatricyclo[40.34.4.216,60]dooctacontane-65-carbonyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1525390: Inhibition of human Nav1.3 expressed in HEK293 cells by electrophysiology assay	ic50	0.0250	uM
4-[(5-chloro-1,3-thiazol-2-yl)sulfamoyl]-N-[[4-chloro-3-(trifluoromethyl)phenyl]methyl]benzamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.0300	uM
4-[5-[(3,4-dichlorophenyl)methyl]-1H-1,2,4-triazol-3-yl]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.0450	uM
Pimozide	1207165: Inhibition of Na channel (species unknown)	ic50	0.0540	uM
trans-(1R,2R)-2-phenyl-N-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]cyclopropane-1-carboxamide	2133187: Inhibition of human Nav1.3 expressed in CHO cells under inactivated state by automated patch clamp electrophysiology analysis	ic50	0.0560	uM
N-cyclopropylsulfonyl-1-[(3R)-1-[(1R)-1-(3,5-dichlorophenyl)ethyl]pyrrolidin-3-yl]-6-fluoro-3-methylindazole-5-carboxamide	1525420: Binding affinity to human recombinant Nav1.3 by radioligand binding assay	kd	0.1100	uM
(4S)-4-[[2-[[(2S)-2-amino-3-methylbutanoyl]amino]acetyl]amino]-5-[[(2S)-1-[[(1R,4S,7S,13S,19S,22S,28S,31S,34R,39R,42S,45S,48S,51S,54S,61R)-22,31-bis(4-aminobutyl)-28-(2-amino-2-oxoethyl)-39-[[(2S)-1-amino-1-oxopropan-2-yl]carbamoyl]-7,19,42,54-tetrakis(3-carbamimidamidopropyl)-51-(carboxymethyl)-45-(hydroxymethyl)-48-(1H-imidazol-5-ylmethyl)-4-(1H-indol-3-ylmethyl)-13-methyl-3,6,9,12,15,18,21,24,27,30,33,41,44,47,50,53,56,62-octadecaoxo-36,37,58,59-tetrathia-2,5,8,11,14,17,20,23,26,29,32,40,43,46,49,52,55,63-octadecazabicyclo[32.22.7]trihexacontan-61-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1583524: Inhibition of Nav1.3 (unknown origin) expressed in Xenopus laevis oocytes at -80 mV holding potential by two electrode voltage-clamp assay	ic50	0.1100	uM
N-(1,3-thiazol-2-yl)-4-[5-[[4-(trifluoromethyl)phenyl]methyl]-1H-1,2,4-triazol-3-yl]benzenesulfonamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.1240	uM
4-(1,3-thiazol-2-ylsulfamoyl)-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.1470	uM
N-(1,3-thiazol-2-yl)-4-[2-[4-(trifluoromethyl)phenyl]ethylsulfonyl]benzenesulfonamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.1550	uM
4-N-(1,3-thiazol-2-yl)-1-N-[[4-(trifluoromethyl)phenyl]methyl]benzene-1,4-disulfonamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.1600	uM
4-[[1-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	1525420: Binding affinity to human recombinant Nav1.3 by radioligand binding assay	kd	0.1800	uM
4-(1,3-thiazol-2-ylsulfamoyl)-N-[[4-(trifluoromethoxy)phenyl]methyl]benzamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.1970	uM
(4S)-4-[[2-[[(2S)-2-amino-3-methylbutanoyl]amino]acetyl]amino]-5-[[(2S)-1-[[(1R,7S,10S,13R,16S,19S,22S,25S,28S,31R,36R,39S,42S,48S,51S,61R,66R)-39,48-bis(4-aminobutyl)-42-(2-amino-2-oxoethyl)-7,16,28,51-tetrakis(3-carbamimidamidopropyl)-61-carbamoyl-19-(carboxymethyl)-25-(hydroxymethyl)-22-(1H-imidazol-5-ylmethyl)-10-(1H-indol-3-ylmethyl)-2,5,8,11,14,17,20,23,26,29,37,40,43,46,49,52,55,63,65-nonadecaoxo-33,34,58,59,68,69-hexathia-3,6,9,12,15,18,21,24,27,30,38,41,44,47,50,53,56,62,64-nonadecazatricyclo[29.25.7.713,36]heptacontan-66-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1583524: Inhibition of Nav1.3 (unknown origin) expressed in Xenopus laevis oocytes at -80 mV holding potential by two electrode voltage-clamp assay	ic50	0.2000	uM
(3S)-3-amino-4-oxo-4-[[(1R,4S,7S,10S,13S,16S,19R,24R,27S,30S,33S,36S,39S,42S,45R,51S,54S,57S,60R,65R,68S,71S,74S,77S,83S)-7,30,36,42,57-pentakis(4-aminobutyl)-77-benzyl-39,68-bis(3-carbamimidamidopropyl)-24-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamoyl]-4,13-bis(2-carboxyethyl)-10,16,83-tris(carboxymethyl)-27,71-bis[(4-hydroxyphenyl)methyl]-54-(1H-imidazol-5-ylmethyl)-51-(2-methylpropyl)-33,74-bis(2-methylsulfanylethyl)-2,5,8,11,14,17,26,29,32,35,38,41,44,47,50,53,56,59,66,69,72,75,78,81,84,91-hexacosaoxo-21,22,62,63,87,88-hexathia-3,6,9,12,15,18,25,28,31,34,37,40,43,46,49,52,55,58,67,70,73,76,79,82,85,90-hexacosazatricyclo[43.40.4.219,60]hennonacontan-65-yl]amino]butanoic acid	1525390: Inhibition of human Nav1.3 expressed in HEK293 cells by electrophysiology assay	ic50	0.2100	uM
4-[[1-[3-chloro-4-(trifluoromethoxy)benzoyl]azetidin-3-yl]oxymethyl]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.2370	uM
5-chloro-N-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]-2,3-dihydro-1-benzofuran-2-carboxamide	2133187: Inhibition of human Nav1.3 expressed in CHO cells under inactivated state by automated patch clamp electrophysiology analysis	ic50	0.2400	uM
(4S)-4-[[2-[[(2S)-2-amino-3-methylbutanoyl]amino]acetyl]amino]-5-[[(2S)-1-[[(1R,7S,10S,16S,19S,22S,25R,30R,33S,36S,39S,42S,45S,48S,51R,61S,64S)-10,19-bis(4-aminobutyl)-16-(2-amino-2-oxoethyl)-7,33,45,61-tetrakis(3-carbamimidamidopropyl)-51-carbamoyl-36-(carboxymethyl)-42-(hydroxymethyl)-39-(1H-imidazol-5-ylmethyl)-64-(1H-indol-3-ylmethyl)-22,48-dimethyl-3,6,9,12,15,18,21,24,31,34,37,40,43,46,49,56,59,62,65-nonadecaoxo-27,28,53,54-tetrathia-2,5,8,11,14,17,20,23,32,35,38,41,44,47,50,57,60,63,66-nonadecazabicyclo[28.25.11]hexahexacontan-25-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1583524: Inhibition of Nav1.3 (unknown origin) expressed in Xenopus laevis oocytes at -80 mV holding potential by two electrode voltage-clamp assay	ic50	0.2600	uM
Loperamide	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.2700	uM
4-[4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.2800	uM
4-[4-chloro-2-(2-methylpyrazol-3-yl)phenoxy]-3-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide	1457692: Inhibition of human NaV1.3 expressed in HEK cells assessed as half inactivation potential at -120 mV holding potential by automated patch clamp method	ic50	0.2920	uM
4-[3-chloro-4-(trifluoromethoxy)phenoxy]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.2960	uM
N-[2-methyl-3-[[4-[4-[[4-(trifluoromethoxy)phenyl]methoxy]piperidin-1-yl]-1,3,5-triazin-2-yl]amino]phenyl]acetamide	612195: Inhibition of 20% inactivated TTX-resistant human sodium channel Nav1.3 expressed in human HEK293 cells at 1 uM by patch-clamp electrophysiological assay	ic50	0.3000	uM
3,3-diphenyl-N-(1-phenylpropan-2-yl)propan-1-amine	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.3000	uM
2-(4-chlorophenoxy)-N-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]propanamide	2133187: Inhibition of human Nav1.3 expressed in CHO cells under inactivated state by automated patch clamp electrophysiology analysis	ic50	0.3200	uM
1-benzyl-4,5-dibromo-N-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]pyrrole-2-carboxamide	2133187: Inhibition of human Nav1.3 expressed in CHO cells under inactivated state by automated patch clamp electrophysiology analysis	ic50	0.3300	uM
N-[[3-chloro-4-(trifluoromethoxy)phenyl]methyl]-3-fluoro-4-(pyrimidin-2-ylsulfamoyl)benzamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.3740	uM
1-benzyl-N-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]pyrrole-2-carboxamide	2133187: Inhibition of human Nav1.3 expressed in CHO cells under inactivated state by automated patch clamp electrophysiology analysis	ic50	0.3800	uM
1-[(4-chlorophenyl)methyl]-N-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]pyrrole-2-carboxamide	2133187: Inhibition of human Nav1.3 expressed in CHO cells under inactivated state by automated patch clamp electrophysiology analysis	ic50	0.3800	uM
1-benzhydryl-4-[(E)-3-phenylprop-2-enyl]piperazine	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.4400	uM
4,5-dibromo-1-phenyl-N-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]pyrrole-2-carboxamide	2133187: Inhibition of human Nav1.3 expressed in CHO cells under inactivated state by automated patch clamp electrophysiology analysis	ic50	0.4400	uM
N-[[3-chloro-4-(trifluoromethoxy)phenyl]methyl]-3-fluoro-N-methyl-4-(1,2,4-thiadiazol-5-ylsulfamoyl)benzamide	1411465: Inhibition of human NaV1.3 expressed in HEK cells by electrophysiological method	ic50	0.5220	uM
3-[4-[3-(3,4,5-trimethoxybenzoyl)oxypropyl]-1,4-diazepan-1-yl]propyl 3,4,5-trimethoxybenzoate	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.6000	uM
8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.6000	uM
1-[bis(4-fluorophenyl)methyl]-4-[(E)-3-phenylprop-2-enyl]piperazine	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.6000	uM
Droperidol	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.7400	uM
Tetracaine	1296897: Inhibition of recombinant human Nav1.3 expressed in HEK293 cells preincubated for 40 mins followed by DiSBAC2 substrate addition measured after 90 mins by FRET assay	ic50	0.7400	uM
(R)-[(2S,4R,5S)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-[6-(3-methylbutoxy)quinolin-4-yl]methanol	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.7400	uM
1-(2-phenylcyclopentyl)-azacyclotridecan-2-imine	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.8000	uM
N-benzyl-N-[3-(2-methylpropoxy)-2-pyrrolidin-1-ylpropyl]aniline	205267: Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex	ic50	0.8400	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases methylation, affects cotreatment	9
trichostatin A	increases expression	2
bisphenol F	affects cotreatment, decreases methylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
decamethrin	decreases expression, decreases reaction	1
1,2-bis(2-aminophenoxy)ethane N,N,N’,N’-tetraacetic acid acetoxymethyl ester	decreases expression, decreases reaction	1
PD 150606	decreases expression, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
2,3,5,6-tetrafluoro-4-methylbenzyl (Z)-(1RS)-cis-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate	affects cotreatment, decreases reaction, increases transport	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
N-(2-methyl-3-(4-(4-(4-(trifluoromethoxy)benzyloxy)piperidin-1-yl)-1,3,5-triazin-2-ylamino)phenyl)acetamide	decreases activity	1
Fulvestrant	decreases methylation, affects cotreatment	1
Vorinostat	affects cotreatment, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	decreases expression	1
Cannabidiol	decreases activity	1
Nickel	decreases expression	1
Phenytoin	affects binding, decreases activity	1
Sodium	decreases reaction, increases transport, affects cotreatment	1
Tetrodotoxin	decreases reaction, decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

102 unique, capped per target: 79 binding, 18 functional, 4 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL679768	Binding	Inhibition of [3H]BTX binding to guinea pig voltage-dependent sodium channel	Anticonvulsant activity of piperidinol and (dialkylamino)alkanol esters. — J Med Chem
CHEMBL749469	Functional	Antagonism of batrachotoxin-mediated sodium ion uptake into cultured neuroblastoma cells	Batrachotoxin binding site antagonists — Bioorg Med Chem Lett
CHEMBL4623833	ADMET	Inhibition of human Nav1.3 expressed in CHO cells at 100 uM with -120 mV holding potential by whole cell manual patch clamp method relative to control	Discovery of DS-1971a, a Potent, Selective NaV1.7 Inhibitor. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_RQ79	PrecisION hNav1.3-CHO	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy