SLC6A2

Summary

SLC6A2 (solute carrier family 6 member 2, HGNC:11048) is a protein-coding gene on chromosome 16q12.2, encoding Sodium-dependent noradrenaline transporter (P23975). Mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline), the primary signaling neurotransmitter in the autonomic sympathetic nervous system.

This gene encodes a member of the sodium:neurotransmitter symporter family. This member is a multi-pass membrane protein, which is responsible for reuptake of norepinephrine into presynaptic nerve terminals and is a regulator of norepinephrine homeostasis. Mutations in this gene cause orthostatic intolerance, a syndrome characterized by lightheadedness, fatigue, altered mentation and syncope. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.

Source: NCBI Gene 6530 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperekplexia 3 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 1,101 total — 44 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes — 471 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001172501

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11048
Approved symbol	SLC6A2
Name	solute carrier family 6 member 2
Location	16q12.2
Locus type	gene with protein product
Status	Approved
Aliases	NET
Ensembl gene	ENSG00000103546
Ensembl biotype	protein_coding
OMIM	163970
Entrez	6530

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 10 protein_coding, 1 nonsense_mediated_decay

ENST00000219833, ENST00000379906, ENST00000414754, ENST00000561820, ENST00000566163, ENST00000567238, ENST00000568529, ENST00000568943, ENST00000574918, ENST00000682050, ENST00000865255

RefSeq mRNA: 4 — MANE Select: NM_001172501 NM_001043, NM_001172501, NM_001172502, NM_001172504

CCDS: CCDS10754, CCDS54011, CCDS58463

Canonical transcript exons

ENST00000568943 — 15 exons

Exon	Start	End
ENSE00000684492	55691918	55692052
ENSE00000684495	55695278	55695402
ENSE00000684496	55696225	55696337
ENSE00000684498	55697897	55698025
ENSE00000684499	55698469	55698568
ENSE00000684500	55699554	55699654
ENSE00000684501	55700139	55700306
ENSE00001169626	55669565	55669696
ENSE00001415344	55685143	55685281
ENSE00001420102	55671938	55672175
ENSE00002620097	55655988	55656169
ENSE00002731559	55656644	55656968
ENSE00003659187	55701863	55701934
ENSE00003788226	55694010	55694113
ENSE00003916596	55702323	55706192

Expression profiles

Bgee: expression breadth ubiquitous, 121 present calls, max score 84.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.3685 / max 45.5454, expressed in 1282 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87568	2.3685	1282
154173	0.0976	19
154176	0.0550	14
154177	0.0429	15
154174	0.0322	14
154175	0.0147	8
154178	0.0098	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	84.62	gold quality
buccal mucosa cell	CL:0002336	83.55	silver quality
decidua	UBERON:0002450	80.94	gold quality
superior vestibular nucleus	UBERON:0007227	80.19	gold quality
caput epididymis	UBERON:0004358	77.46	gold quality
sperm	CL:0000019	73.86	gold quality
male germ cell	CL:0000015	73.15	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.01	gold quality
secondary oocyte	CL:0000655	71.16	gold quality
oocyte	CL:0000023	70.70	silver quality
upper leg skin	UBERON:0004262	70.49	gold quality
vastus lateralis	UBERON:0001379	70.40	gold quality
frontal pole	UBERON:0002795	70.04	gold quality
paraflocculus	UBERON:0005351	69.77	gold quality
middle frontal gyrus	UBERON:0002702	69.51	gold quality
quadriceps femoris	UBERON:0001377	69.14	gold quality
biceps brachii	UBERON:0001507	68.99	gold quality
medulla oblongata	UBERON:0001896	68.65	silver quality
adult organism	UBERON:0007023	67.60	gold quality
Brodmann (1909) area 10	UBERON:0013541	66.62	gold quality
cerebellar vermis	UBERON:0004720	66.39	gold quality
renal glomerulus	UBERON:0000074	66.13	gold quality
metanephric glomerulus	UBERON:0004736	65.93	silver quality
vena cava	UBERON:0004087	65.29	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	65.26	gold quality
lateral nuclear group of thalamus	UBERON:0002736	65.17	gold quality
gluteal muscle	UBERON:0002000	64.92	gold quality
left testis	UBERON:0004533	64.55	gold quality
nipple	UBERON:0002030	64.31	silver quality
endothelial cell	CL:0000115	64.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	16.44
E-ANND-3	no	4.10

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, CTNNB1, ELK3, HOXA5, MYB, NR3C1, PHOX2A, PHOX2B, SCRT1, SNAI2, USF1, USF2

miRNA regulators (miRDB)

36 targeting SLC6A2, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-6080	99.43	69.43	373
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-320A-5P	98.88	66.75	1248
HSA-MIR-6811-3P	98.62	66.54	944
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-6776-3P	98.38	66.34	655
HSA-MIR-550A-3P	98.37	69.61	632
HSA-MIR-8078	98.32	65.73	361
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-3661	97.83	67.30	705
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-4733-5P	97.75	67.44	866
HSA-MIR-3665	97.73	65.08	975
HSA-MIR-200C-5P	97.71	67.73	596
HSA-MIR-631	97.05	66.93	602

Literature-anchored findings (GeneRIF, showing 40)

• The NH(2)-terminus of norepinephrine transporter contains a basolateral localization signal for epithelial cells. (PMID:11739781)
• Tyrosine residue 271 of the norephinephrine transporter is an important determinant of its pharmacology. (PMID:11744160)
• Results do not support the NET1 gene as a major genetic susceptibility factor in ADHD. (PMID:11920844)
• norepinephrine transporter polymorphisms are not major susceptibility factors in the etiology of major depression (PMID:11927173)
• No association was found between the studied polymorphism of the NET gene and either bipolar disorder or schizophrenia. (PMID:12097806)
• C-terminal residues encoded by hNET 1a enable the efficient maturation and surface expression of hNET and therefore critically impact transporter activity. (PMID:12127072)
• Anorexia nervosa (restrictive subtype) is associated with a polymorphism in the promoter polymorphic region (PMID:12140790)
• No evidence of linkage or association between the norepinephrine transporter (NET) gene polymorphisms and ADHD in the Irish population. (PMID:12210284)
• Results suggest that glycine residues of the GXXXRXG motif are important determinants of human norepinephrine transporter expression and function, while the arginine residue does not have a major role. (PMID:12480177)
• Data suggest that mutation in exon 9 of the norepinephrine transporter gene (Ala457Pro) is not a cause of the impaired uptake of norepinephrine in patients with orthostatic intolerance. (PMID:12589229)
• hNET exists as a homo-oligomer; coimmunoprecipitation demonstrated physical interaction between norepinephrine transporter monomers; norepinephrine transporter-serotonin transporter physical association did not produce functional consequences (PMID:12787070)
• In transiently transfected COS-7 cells processing of human NET-A457P to the fully glycosylated form was impaired and a decrease in surface expression to approximately 30% of NET-wild type was noted (PMID:12805287)
• SLC6A2 may be one of the genes that contribute to hypertension. (PMID:14620922)
• Proline residues in extracellular loop 2 and in transmembrane domains have a range of roles in determining expression and function of the noradrenaline transporter (PMID:14675164)
• NET contribution to cardiac norepinephrine turnover may be decreased in women and the gender difference in NET function may not be expressed in tissues that are less NET dependent than the heart. (PMID:14726430)
• This result suggests that the T-182C polymorphism in the NET gene might be associated with major depression. (PMID:15118352)
• demonstrated high expression of norepinephrine transporter (NET) mRNA in the trophoblast cells of the anchoring villi and a lower expression intensity in the chorionic villi and a significant lower expression of NET mRNAs in pre-eclamptic place (PMID:15135235)
• In transfected HEK293 cells we compared by [(3)H]norepinephrine ([(3)H]NE) uptake and [(3)H]nisoxetine ([(3)H]NIS) binding the functional properties of wild-type hNET with those of the long splice variant with exon 15 (hNET-Ex15L) and 2 artificial mutants (PMID:15485485)
• The norepinephrine transporter T-182C polymorphism may be in part related to the pathophysiology of major depressive disorder in a Japanese population. (PMID:15539861)
• This tudy provides support for an association between Attention deficit hyperactivity disorder and polymorphisms in norepinephrine transporter gene. (PMID:15717291)
• In the subgroup of patients with panic disorder without concurrent agoraphobia, two polymorphisms of the norepinephrine transporter (NET) are found to be associated with the disease. (PMID:15722184)
• analysis of norepinephrine transporter substrate binding stoichiometry and kinetics (PMID:15757904)
• Induction of c-Fos by dopamine and norepinephrine requires the presence of hDAT and hNET but the contributions of hDAT and hNET to c-Fos induction is distinguishable on the basis of differing responses to a PKC inhibitor. (PMID:15763138)
• Chronic exposure to cocaine upregulated NET protein expression and [3H]nisoxetine binding sites in the insular cortex from brains of cocaine addicts. (PMID:15763139)
• T-182C gene polymorphism is associated with reward dependence in Koreans. (PMID:15900230)
• verified physical association of norepinephrine transporter with protein phosphatase 2A-Ar via co-immunoprecipitation studies using vas deferens extracts and with 14-3-3 via a fusion pull-down approach (PMID:15963952)
• The results suggest that a region of hNET is important for interactions with antidepressants and cocaine, but it is probably not involved in substrate translocation mechanisms. (PMID:16092934)
• Adrenaline-producing phaeochromocytomas in multiple endocrine neoplasia type 2 expressed more noradrenaline transporter mRNA and protein than noradrenaline-producing tumours in von Hippel-Lindau syndrome. (PMID:16189177)
• Reduction in noradrenaline transporter could be related to changes in intracellular levels, and these modifications could result in functional changes of the immune system. (PMID:16242784)
• Depolarization of sympathetic neurons induces NET expression through increasing catecholamines, and that M17 neuroblastoma cells provide a model system in which to investigate catechol regulation of NET expression. (PMID:16573647)
• Characterization of the two major isoforms of human NET, with characterization of two exons. (PMID:16965261)
• Norepinephrine transpossrter/syntaxin 1A complex rapidly redistributes, upon amphetamine treatment, when mechanisms supported by the transporter’s NH2 terminus are eliminated. (PMID:17032905)
• No association was found between G1287A polymorphism in the NET gene and diabetes, but this polymorphism has a possible role in increased susceptibility to hypertension in patients with type 2 diabetes (PMID:17124432)
• A primary physiological role of alpha-Syn may be to regulate the homeostasis of monoamines in synapses, through modulatory interactions of the protein with monoaminergic transporters. (PMID:17156375)
• study suggests that the investigated polymorphisms in the NET gene are not major risk factors in increasing susceptibility to either major depression or its clinical subtypes in a Han Chinese population (PMID:17353941)
• NAT1 polymorphisms are predictive markers of the response to beta-blockers (PMID:17404580)
• Data show that conotoxin chi-MrIA-interacting residues were located at the mouth of the norepinephrine transporter near residues affecting the binding of small molecule inhibitors. (PMID:17428804)
• These studies demonstrate the potential for a wider application of hNET reporter imaging and the future translation to patient studies using radiopharmaceuticals that are currently available for both SPECT and PET. (PMID:17475971)
• *Promoter polymorphism is not assiciated with anorexia nervosa. (PMID:17621171)
• polymorphisms in hSLC6A2 gene are not major risk factors in increasing susceptibility to either alcohol dependence or its clinical (PMID:17630229)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc6a2	ENSDARG00000016141
mus_musculus	Slc6a2	ENSMUSG00000055368
rattus_norvegicus	Slc6a2	ENSRNOG00000016311

Paralogs (19): SLC6A13 (ENSG00000010379), SLC6A7 (ENSG00000011083), SLC6A16 (ENSG00000063127), SLC6A15 (ENSG00000072041), SLC6A4 (ENSG00000108576), SLC6A12 (ENSG00000111181), SLC6A8 (ENSG00000130821), SLC6A6 (ENSG00000131389), SLC6A11 (ENSG00000132164), SLC6A3 (ENSG00000142319), SLC6A1 (ENSG00000157103), SLC6A20 (ENSG00000163817), SLC6A18 (ENSG00000164363), SLC6A5 (ENSG00000165970), SLC6A19 (ENSG00000174358), SLC6A9 (ENSG00000196517), SLC6A17 (ENSG00000197106), SLC6A14 (ENSG00000268104), (ENSG00000273554)

Protein

Protein identifiers

Sodium-dependent noradrenaline transporter — P23975 (reviewed: P23975)

Alternative names: Norepinephrine transporter, Solute carrier family 6 member 2

All UniProt accessions (6): P23975, A0A804HLI4, H3BM11, H3BML6, H3BRE9, H3BRS0

UniProt curated annotations — full annotation on UniProt →

Function. Mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline), the primary signaling neurotransmitter in the autonomic sympathetic nervous system. Is responsible for norepinephrine re-uptake and clearance from the synaptic cleft, thus playing a crucial role in norepinephrine inactivation and homeostasis. Can also mediate sodium- and chloride-dependent transport of dopamine.

Subunit / interactions. Monomer. Can form homodimers in the cell membrane; homodimerization is mostly mediated by cholesterol and lipids, and regulates neurotransmitter transport activity. Interacts with PRKCABP.

Subcellular location. Cell membrane. Cell projection. Axon. Synapse. Synaptosome.

Post-translational modifications. Palmitoylated; palmitoylation regulates protein levels and neurotransmitter transport.

Disease relevance. Orthostatic intolerance (ORSTI) [MIM:604715] An autosomal dominant disorder characterized by lightheadedness, palpitations, fatigue, blurred vision and tachycardia following postural change from a supine to an upright position, in the absence of hypotension. A syncope with transient cognitive impairment and dyspnea may also occur. Plasma norepinephrine concentration is abnormally high. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by mazindol, desipramine, nomifensine and nortriptyline.

Miscellaneous. This protein is the target of psychomotor stimulants such as amphetamines or cocaine.

Similarity. Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A2 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P23975-1	1	yes
P23975-2	2
P23975-3	3

RefSeq proteins (4): NP_001034, NP_001165972, NP_001165973, NP_001165975 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000175	Na/ntran_symport	Family
IPR002435	Na/ntran_symport_noradrenaline	Family
IPR037272	SNS_sf	Homologous_superfamily

Pfam: PF00209

Catalyzed reactions (Rhea), 3 shown:

• dopamine(out) + chloride(out) + Na(+)(out) = dopamine(in) + chloride(in) + Na(+)(in) (RHEA:70919)
• (R)-noradrenaline(out) + chloride(out) + Na(+)(out) = (R)-noradrenaline(in) + chloride(in) + Na(+)(in) (RHEA:70923)
• dopamine(out) + chloride(out) + 2 Na(+)(out) = dopamine(in) + chloride(in) + 2 Na(+)(in) (RHEA:70931)

UniProt features (144 total): helix 33, mutagenesis site 24, binding site 19, sequence variant 16, topological domain 13, transmembrane region 12, strand 10, turn 8, glycosylation site 3, splice variant 2, chain 1, region of interest 1, compositionally biased region 1, disulfide bond 1

Structure

Experimental structures (PDB)

36 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8ZP2	ELECTRON MICROSCOPY	2.4
9KDA	ELECTRON MICROSCOPY	2.44
9KDM	ELECTRON MICROSCOPY	2.46
8HFE	ELECTRON MICROSCOPY	2.5
8HFI	ELECTRON MICROSCOPY	2.5
8ZOY	ELECTRON MICROSCOPY	2.5
8ZP1	ELECTRON MICROSCOPY	2.5
9KDH	ELECTRON MICROSCOPY	2.52
8ZPB	ELECTRON MICROSCOPY	2.6
8WTU	ELECTRON MICROSCOPY	2.7
8WTV	ELECTRON MICROSCOPY	2.7
8WGR	ELECTRON MICROSCOPY	2.75
9K6X	ELECTRON MICROSCOPY	2.77
8WTW	ELECTRON MICROSCOPY	2.8
8XB3	ELECTRON MICROSCOPY	2.8
8I3V	ELECTRON MICROSCOPY	2.85
8HFF	ELECTRON MICROSCOPY	2.86
9JF3	ELECTRON MICROSCOPY	2.87
8YR2	ELECTRON MICROSCOPY	2.89
8WTX	ELECTRON MICROSCOPY	2.9
8XB4	ELECTRON MICROSCOPY	2.92
9JEL	ELECTRON MICROSCOPY	2.98
8HFG	ELECTRON MICROSCOPY	3
8HFL	ELECTRON MICROSCOPY	3
8Y93	ELECTRON MICROSCOPY	3
8XB2	ELECTRON MICROSCOPY	3.04
8Y91	ELECTRON MICROSCOPY	3.13
9KE3	ELECTRON MICROSCOPY	3.13
8Y90	ELECTRON MICROSCOPY	3.15
8WTY	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23975-F1	87.54	0.73

Antibody-complex structures (SAbDab): 2 — 8ZOY, 8ZPB

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 (19): 71; 73; 74; 75; 75; 78; 87; 88; 145; 145; 149; 317 …

Disulfide bonds (1): 176–185

Glycosylation sites (3): 184, 192, 198

Mutagenesis-validated functional residues (24):

Position	Phenotype
44	decreased protein levels. decreased dopamine uptake.
72	loss of norepinephrine binding.
75	loss of norepinephrine binding. abolishes norepinephrine uptake.
75	abolishes norepinephrine uptake.
135	decreased homodimerization and norepinephrine transport; when associated with a-435, a-438 and a-444.
148	decreased norepinephrine uptake.
149	decreased norepinephrine uptake.
152	loss of norepinephrine binding.
152	severely decreased norepinephrine uptake.
153	abolishes norepinephrine uptake.
232	decreased homodimerization and norepinephrine transport; when associated with a-235, a-459 and a-553.
235	decreased homodimerization and norepinephrine transport; when associated with a-232, a-459 and a-553.
317	loss of norepinephrine binding.
320	loss of norepinephrine binding.
323	loss of norepinephrine binding. abolishes norepinephrine uptake.
325	decreased norepinephrine uptake.
419	loss of norepinephrine binding.
420	no effect on norepinephrine binding. decreased norepinephrine uptake.
423	loss of norepinephrine binding. abolishes norepinephrine uptake.
435	decreased homodimerization and norepinephrine transport; when associated with a-135, a-438 and a-444.
438	decreased homodimerization and norepinephrine transport; when associated with a-135, a-435 and a-444.
444	decreased homodimerization and norepinephrine transport; when associated with a-135, a-435 and a-438.
459	decreased homodimerization and norepinephrine transport; when associated with a-232, a-235 and a-553.
553	decreased homodimerization and norepinephrine transport; when associated with a-232, a-235 and a-459.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-442660	SLC-mediated transport of neurotransmitters
R-HSA-5619109	Defective SLC6A2 causes orthostatic intolerance (OI)
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-425366
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters

MSigDB gene sets: 862 (showing top): MORF_ITGA2, GOBP_RESPONSE_TO_IONIZING_RADIATION, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_BIOLOGICAL_OXIDATIONS, BENPORATH_ES_WITH_H3K27ME3, MODULE_274, MODULE_162, GOBP_NEUROTRANSMITTER_UPTAKE, JAEGER_METASTASIS_DN, NKX25_02, GOCC_SECRETORY_GRANULE, PEREZ_TP63_TARGETS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, MODULE_45, MODULE_64

GO Biological Process (15): neurotransmitter transport (GO:0006836), amino acid transport (GO:0006865), chemical synaptic transmission (GO:0007268), response to xenobiotic stimulus (GO:0009410), obsolete monoamine transport (GO:0015844), obsolete norepinephrine transport (GO:0015874), sodium ion transmembrane transport (GO:0035725), response to pain (GO:0048265), dopamine uptake involved in synaptic transmission (GO:0051583), norepinephrine uptake (GO:0051620), neuron cellular homeostasis (GO:0070050), transmembrane transport (GO:0055085), catecholamine uptake (GO:0090493), neurotransmitter reuptake (GO:0098810), chloride transmembrane transport (GO:1902476)

GO Molecular Function (12): actin binding (GO:0003779), neurotransmitter transmembrane transporter activity (GO:0005326), neurotransmitter:sodium symporter activity (GO:0005328), dopamine:sodium symporter activity (GO:0005330), norepinephrine:sodium symporter activity (GO:0005334), monoamine transmembrane transporter activity (GO:0008504), alpha-tubulin binding (GO:0043014), metal ion binding (GO:0046872), beta-tubulin binding (GO:0048487), protein binding (GO:0005515), symporter activity (GO:0015293), sodium:chloride symporter activity (GO:0015378)

GO Cellular Component (10): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), axon (GO:0030424), synaptic vesicle membrane (GO:0030672), neuronal cell body membrane (GO:0032809), presynaptic membrane (GO:0042734), cell projection (GO:0042995), neuron projection (GO:0043005), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
SLC-mediated transmembrane transport	1
SLC transporter disorders	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	3
cellular anatomical structure	3
dopamine uptake	2
presynapse	2
monoamine transmembrane transporter activity	2
sodium:chloride symporter activity	2
tubulin binding	2
anterograde trans-synaptic signaling	1
response to chemical	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
multicellular organismal response to stress	1
synaptic transmission, dopaminergic	1
neurotransmitter reuptake	1
catecholamine uptake	1
cellular homeostasis	1
cellular process	1
organic hydroxy compound transport	1
nitrogen compound transport	1
neurotransmitter uptake	1
establishment of localization in cell	1
chloride transport	1
monoatomic anion transmembrane transport	1
cytoskeletal protein binding	1
neurotransmitter transport	1
transmembrane transporter activity	1
neurotransmitter transmembrane transporter activity	1
solute:sodium symporter activity	1
norepinephrine uptake	1
active transmembrane transporter activity	1
cation binding	1
binding	1
secondary active transmembrane transporter activity	1
monoatomic anion:sodium symporter activity	1
chloride:monoatomic cation symporter activity	1
membrane	1
cell periphery	1
neuron projection	1
synaptic vesicle	1
exocytic vesicle membrane	1

Protein interactions and networks

STRING

1184 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC6A2	STX1A	Q16623	888
SLC6A2	ADCY7	P51828	840
SLC6A2	SLC5A2	P31639	832
SLC6A2	SLC22A3	O75751	822
SLC6A2	SCRT1	Q9BWW7	810
SLC6A2	SLC18A2	Q05940	805
SLC6A2	ADRA2A	P08913	788
SLC6A2	HTR1A	P08908	781
SLC6A2	YRDC	Q86U90	774
SLC6A2	Q92681	Q92681	763
SLC6A2	TH	P07101	752
SLC6A2	MAOA	P21397	739
SLC6A2	SLC22A6	Q4U2R8	714
SLC6A2	DBH	P09172	708
SLC6A2	ADRA2C	P18825	698

IntAct

7 interactions, top by confidence:

A	B	Type	Score
SLC6A2	PICK1	psi-mi:“MI:0915”(physical association)	0.510
PICK1	SLC6A2	psi-mi:“MI:0915”(physical association)	0.510
	SLC6A2	psi-mi:“MI:0915”(physical association)	0.400
SLC6A2	CLGN	psi-mi:“MI:0914”(association)	0.350

BioGRID (22): APMAP (Affinity Capture-MS), BAG5 (Affinity Capture-MS), CLGN (Affinity Capture-MS), CLPTM1 (Affinity Capture-MS), FZD8 (Affinity Capture-MS), HSPA4L (Affinity Capture-MS), NUDT4 (Affinity Capture-MS), NUP210 (Affinity Capture-MS), PSMC6 (Affinity Capture-MS), RAB5B (Affinity Capture-MS), SGPL1 (Affinity Capture-MS), STUB1 (Affinity Capture-MS), THEM6 (Affinity Capture-MS), TMEM109 (Affinity Capture-MS), UBTD1 (Affinity Capture-MS)

ESM2 similar proteins: A5PJX7, A7Y2W8, O18875, O35316, O35899, O55192, O88576, P23975, P23977, P23978, P27799, P28570, P28571, P28572, P28573, P30531, P31641, P31643, P31645, P31646, P31647, P31648, P31649, P31650, P31651, P31652, P31661, P48029, P48055, P48056, P48057, P48065, P48066, P51143, P51905, Q00589, Q01959, Q28039, Q2PG55, Q60857

Diamond homologs: A5PJX7, A7Y2W8, A7Y2X0, B3MRS1, B3NV41, B4GVM9, B4JMC1, B4L7U0, B4MEG2, B4NDL8, B4PZQ4, B4R4T6, G5EBN9, O18875, O35316, O35899, O45813, O55192, O76689, O88575, O88576, P23975, P23977, P23978, P27799, P27922, P28570, P28571, P28572, P28573, P30531, P31641, P31643, P31645, P31646, P31647, P31648, P31649, P31650, P31651

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
nisoxetine	“down-regulates activity”	SLC6A2	“chemical inhibition”
zotepine	“down-regulates activity”	SLC6A2	“chemical inhibition”
Norzotepine	“down-regulates activity”	SLC6A2	“chemical inhibition”
levomilnacipran	“down-regulates activity”	SLC6A2	“chemical inhibition”
protriptyline	“down-regulates activity”	SLC6A2	“chemical inhibition”
trimipramine	“down-regulates activity”	SLC6A2	“chemical inhibition”
Phenelzine	“down-regulates activity”	SLC6A2	“chemical inhibition”
clomipramine	“down-regulates activity”	SLC6A2	“chemical inhibition”
dothiepin	“down-regulates activity”	SLC6A2	“chemical inhibition”
lofepramine	“down-regulates activity”	SLC6A2	“chemical inhibition”
PAK1	“down-regulates activity”	SLC6A2	phosphorylation
(S)-duloxetine	“down-regulates activity”	SLC6A2	“chemical inhibition”
venlafaxine	“down-regulates activity”	SLC6A2	“chemical inhibition”
nefazodone	“down-regulates activity”	SLC6A2	“chemical inhibition”
atomoxetine	“down-regulates activity”	SLC6A2	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1101 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	26
Uncertain significance	492
Likely benign	382
Benign	96

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1207401	NM_004211.5(SLC6A5):c.679+1G>T	Pathogenic
1323615	NM_004211.5(SLC6A5):c.1315C>T (p.Arg439Ter)	Pathogenic
1353821	NM_004211.5(SLC6A5):c.2124C>A (p.Tyr708Ter)	Pathogenic
1373505	NM_004211.5(SLC6A5):c.1266_1267dup (p.Tyr423fs)	Pathogenic
1394178	NM_004211.5(SLC6A5):c.997_998del (p.Ile333fs)	Pathogenic
14006	NM_001172501.3(SLC6A2):c.1369G>C (p.Ala457Pro)	Pathogenic
1437471	NM_004211.5(SLC6A5):c.1621C>T (p.Gln541Ter)	Pathogenic
1453382	NC_000011.9:g.(?20621219)(20668500_?)del	Pathogenic
1454424	NM_004211.5(SLC6A5):c.1759del (p.Ile586_Val587insTer)	Pathogenic
1455981	NM_004211.5(SLC6A5):c.1680_1681dup (p.Pro561fs)	Pathogenic
1457616	NC_000011.9:g.(?20668360)(20668500_?)del	Pathogenic
1458893	NM_004211.5(SLC6A5):c.90C>A (p.Cys30Ter)	Pathogenic
1971213	NM_004211.5(SLC6A5):c.811+1G>T	Pathogenic
2015912	NM_004211.5(SLC6A5):c.342del (p.Gly115fs)	Pathogenic
2018966	NM_004211.5(SLC6A5):c.769C>T (p.Gln257Ter)	Pathogenic
2079085	NM_004211.5(SLC6A5):c.1969+1G>A	Pathogenic
2087072	NM_004211.5(SLC6A5):c.1374G>A (p.Trp458Ter)	Pathogenic
2149851	NM_004211.5(SLC6A5):c.1286C>T (p.Pro429Leu)	Pathogenic
2425045	NC_000011.9:g.(?20612464)(20622873_?)del	Pathogenic
2858966	NM_004211.5(SLC6A5):c.31A>T (p.Lys11Ter)	Pathogenic
2991866	NM_004211.5(SLC6A5):c.1680_1681del (p.Pro561fs)	Pathogenic
31540	NM_004211.5(SLC6A5):c.1530T>G (p.Ser510Arg)	Pathogenic
3244667	NC_000011.9:g.(?20621219)(20625990_?)del	Pathogenic
3244668	NC_000011.9:g.(?20625977)(20687645_?)del	Pathogenic
3244670	NC_000011.9:g.(?20617213)(20623070_?)del	Pathogenic
3664122	NM_004211.5(SLC6A5):c.1893del (p.Val632fs)	Pathogenic
38370	NM_004211.5(SLC6A5):c.1444T>C (p.Trp482Arg)	Pathogenic
38371	NM_004211.5(SLC6A5):c.323del (p.Pro108fs)	Pathogenic
4081932	NM_004211.5(SLC6A5):c.1917T>A (p.Tyr639Ter)	Pathogenic
4703079	NM_004211.5(SLC6A5):c.621C>G (p.Tyr207Ter)	Pathogenic

SpliceAI

6289 predictions. Top by Δscore:

Variant	Effect	Δscore
10:5446856:GAG:G	donor_gain	1.0000
10:5446857:AGGT:A	donor_loss	1.0000
10:5446858:GGTAA:G	donor_loss	1.0000
10:5446859:G:GA	donor_loss	1.0000
10:5446860:T:A	donor_loss	1.0000
10:5451824:TTATA:T	acceptor_loss	1.0000
10:5451825:TATA:T	acceptor_loss	1.0000
10:5451827:TAG:T	acceptor_loss	1.0000
10:5451828:A:AG	acceptor_gain	1.0000
10:5451828:A:G	acceptor_loss	1.0000
10:5451829:G:GC	acceptor_loss	1.0000
10:5451829:G:GG	acceptor_gain	1.0000
10:5451829:GGA:G	acceptor_gain	1.0000
10:5451936:AGGTA:A	donor_loss	1.0000
10:5451937:GGT:G	donor_loss	1.0000
10:5451938:GTAAA:G	donor_loss	1.0000
10:5451939:T:A	donor_loss	1.0000
10:5452355:A:AG	acceptor_gain	1.0000
10:5452356:A:G	acceptor_gain	1.0000
10:5452357:G:GA	acceptor_gain	1.0000
10:5452357:GTC:G	acceptor_gain	1.0000
10:5452357:GTCAT:G	acceptor_gain	1.0000
10:5452507:G:GT	donor_gain	1.0000
10:5452522:GGAG:G	donor_gain	1.0000
10:5452523:G:GT	donor_gain	1.0000
10:5452523:GAGGT:G	donor_loss	1.0000
10:5452524:AGGT:A	donor_loss	1.0000
10:5452526:G:GA	donor_loss	1.0000
10:5452527:T:G	donor_loss	1.0000
10:5453477:A:AG	acceptor_gain	1.0000

AlphaMissense

4039 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:55656871:G:C	W59C	1.000
16:55656871:G:T	W59C	1.000
16:55656887:T:C	F65L	1.000
16:55656889:C:A	F65L	1.000
16:55656889:C:G	F65L	1.000
16:55656936:G:C	R81P	1.000
16:55656938:T:C	F82L	1.000
16:55656940:C:A	F82L	1.000
16:55656940:C:G	F82L	1.000
16:55669570:T:C	F94L	1.000
16:55669572:C:A	F94L	1.000
16:55669572:C:G	F94L	1.000
16:55669631:T:C	L114P	1.000
16:55669640:G:A	G117E	1.000
16:55694013:T:A	W308R	1.000
16:55694013:T:C	W308R	1.000
16:55694062:G:A	G324E	1.000
16:55695339:T:C	F362L	1.000
16:55695341:C:A	F362L	1.000
16:55695341:C:G	F362L	1.000
16:55699625:T:A	W521R	1.000
16:55699625:T:C	W521R	1.000
16:55699637:A:C	S525R	1.000
16:55699639:T:A	S525R	1.000
16:55699639:T:G	S525R	1.000
16:55656869:T:A	W59R	0.999
16:55656869:T:C	W59R	0.999
16:55656905:G:C	G71R	0.999
16:55656906:G:A	G71D	0.999
16:55656908:T:C	F72L	0.999

dbSNP variants (sampled 300 via entrez): RS1000075742 (16:55694053 C>A), RS1000097585 (16:55655198 G>A,T), RS1000327222 (16:55672385 T>C), RS1000528549 (16:55676539 G>A,T), RS1000533118 (16:55655492 A>C), RS1000653897 (16:55670837 A>C,G), RS1000959515 (16:55676894 C>T), RS1000996446 (16:55682352 G>T), RS1001047363 (16:55682630 A>G), RS1001173826 (16:55679312 C>T), RS1001330450 (16:55673660 T>G), RS1001394219 (16:55688288 G>C), RS1001421051 (16:55667382 A>G), RS1001624335 (16:55690869 A>T), RS1001625165 (16:55679555 C>T)

Disease associations

OMIM: gene MIM:163970 | disease phenotypes: MIM:614618

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperekplexia 3	Definitive	Autosomal recessive
postural orthostatic tachycardia syndrome	Supportive	Autosomal dominant
hereditary hyperekplexia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hyperekplexia 3	Definitive	AR

Mondo (6): hyperekplexia 3 (MONDO:0013827), neurocirculatory asthenia (MONDO:0001315), long QT syndrome (MONDO:0002442), ependymoma (MONDO:0016698), postural orthostatic tachycardia syndrome (MONDO:0011479), hereditary hyperekplexia (MONDO:0021022)

Orphanet (2): Hereditary hyperekplexia (Orphanet:3197), Ependymoma (Orphanet:251636)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0003345	Elevated urinary norepinephrine level
HP:0003621	Juvenile onset
HP:0012173	Orthostatic tachycardia

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001762_28	Obesity-related traits	8.000000e-06
GCST003262_397	Post bronchodilator FEV1	3.000000e-06
GCST004735_10	Epstein-Barr virus copy number in lymphoblastoid cell lines	8.000000e-06
GCST008362_86	Birth weight	3.000000e-10
GCST008362_87	Birth weight	2.000000e-08
GCST009391_1556	Metabolite levels	4.000000e-06
GCST009391_829	Metabolite levels	8.000000e-06
GCST009738_2	Carotid intima media thickness (maximum)	3.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005134	amino acid measurement
EFO:0004314	forced expiratory volume
EFO:0004344	birth weight
EFO:0009776	ornithine measurement
EFO:0006523	symmetrical dimethylarginine measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004806	Ependymoma	C04.557.465.625.600.380.290; C04.557.470.670.380.290; C04.557.580.625.600.380.290
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D009449	Neurocirculatory Asthenia	F03.080.500
D054972	Postural Orthostatic Tachycardia Syndrome	C10.177.575.600.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2096990 (SELECTIVITY GROUP), CHEMBL2111346 (SELECTIVITY GROUP), CHEMBL222 (SINGLE PROTEIN), CHEMBL2363064 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

471 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 724,322 (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
CHEMBL1000	CETIRIZINE	4	26,030
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL1023	BEXAROTENE	4	40,951
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1046	AMINOCAPROIC ACID	4	95,343
CHEMBL1064	SIMVASTATIN	4	123,163
CHEMBL1070	NABUMETONE	4	55,063
CHEMBL1079604	METAXALONE	4	5,021
CHEMBL1085	ACETOPHENAZINE	4	5,134
CHEMBL1088	MESORIDAZINE	4	12,814
CHEMBL1089	PHENELZINE	4	18,793
CHEMBL1094636	NIRAPARIB	4	6,433
CHEMBL1095777	INDACATEROL	4	2,735
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL1106	EPINASTINE	4	8,530
CHEMBL111	RIMONABANT	4	15,726
CHEMBL1112	ARIPIPRAZOLE	4	24,205
CHEMBL1113	AMOXAPINE	4	20,128
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1118	DESVENLAFAXINE	4
CHEMBL1138	EZETIMIBE	4
CHEMBL1171837	PONATINIB	4
CHEMBL1172	DESLORATADINE	4
CHEMBL1173055	RUCAPARIB	4
CHEMBL1175	DULOXETINE	4
CHEMBL118	CELECOXIB	4
CHEMBL1187833	UMECLIDINIUM	4
CHEMBL119	TRIMETREXATE	4
CHEMBL1193	PHENIRAMINE	4

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

PharmGKB clinical annotations

9 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12708954	Efficacy	3	atomoxetine	Attention Deficit Disorder with Hyperactivity
rs1861647	Other	3	3;4-methylenedioxymethamphetamine
rs2242446	Efficacy	3	venlafaxine	Major Depressive Disorder
rs2242446	Other	3	3;4-methylenedioxymethamphetamine
rs2298826	Toxicity	3	haloperidol	Schizophrenia
rs28386840	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity
rs36029	Other	3	3;4-methylenedioxymethamphetamine
rs3785143	Efficacy	3	atomoxetine	Attention Deficit Disorder with Hyperactivity
rs5569	Efficacy	4	methylphenidate	Attention Deficit Disorder with Hyperactivity

PharmGKB variants

15 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2298826	SLC6A5	3	2.50	1	haloperidol
rs5564	SLC6A2		0.00	0
rs5568	SLC6A2		0.00	0
rs5569	SLC6A2	4	-0.75	1	methylphenidate
rs998424	SLC6A2		0.00	0
rs1362621	SLC6A2		0.00	0
rs2242446	SLC6A2	3	2.75	2	3;4-methylenedioxymethamphetamine;venlafaxine
rs3785143	SLC6A2	3	3.00	1	atomoxetine
rs12708954	SLC6A2	3	3.00	1	atomoxetine
rs168924	SLC6A2		0.00	0
rs47958	SLC6A2		0.00	0
rs1861647	SLC6A2	3	1.00	1	3;4-methylenedioxymethamphetamine
rs36029	SLC6A2	3	1.00	1	3;4-methylenedioxymethamphetamine
rs3785157	SLC6A2		0.00	0
rs7194256	SLC6A2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Monoamine transporter subfamily

Most potent curated ligand interactions (42 total), top 25:

Ligand	Action	Affinity	Parameter
[3H]mazindol	Inhibition	9.3	pKd
milnacipran	Inhibition	9.1	pIC50
mazindol	Inhibition	8.9	pKi
atomoxetine	Inhibition	8.69	pKd
desipramine	Inhibition	8.68	pKi
[3H]nisoxetine	Inhibition	8.4	pKd
nisoxetine	Inhibition	8.4	pKi
lofepramine	Inhibition	8.27	pKi
duloxetine	Inhibition	8.22	pKi
nortriptyline	Inhibition	8.2	pKi
protriptyline	Inhibition	8.17	pKi
H05	Inhibition	8.17	pKi
nomifensine	Inhibition	8.1	pKi
reboxetine	Inhibition	8.0	pKi
norzotepine	Inhibition	7.96	pIC50
maprotiline	Inhibition	7.92	pKi
N-desalkylquetiapine	Inhibition	7.92	pKi
amoxapine	Inhibition	7.89	pKi
imipramine	Inhibition	7.8	pKi
mianserin	Inhibition	7.59	pKi
doxepin	Inhibition	7.54	pKi
clomipramine	Inhibition	7.42	pKd
levomilnacipran	Inhibition	7.4	pIC50
dosulepin	Inhibition	7.34	pKi
ziprasidone	Inhibition	7.32	pKi

Binding affinities (BindingDB)

560 measured of 630 human assays (654 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(S,S)-reboxetine	KI	0.3 nM
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine	KI	0.6 nM
1-(3,4-dichlorophenyl)-5-[6-(trifluoromethyl)pyridazin-3-yl]oxy-9-azatricyclo[7.2.2.02,7]trideca-2(7),3,5-triene	IC50	0.7 nM	US-9045468: 2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
4-[[(3R)-4-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutyl]amino]butanamide	KI	0.91 nM	US-9296681: Cycloalkylmethylamines
4-(aminomethyl)-1-[2,5-difluoro-3-(3-fluorophenoxy)phenyl]piperidin-4-ol (E15)	IC50	0.912 nM	US-9920053: N-(hetero)aryl-substituted heteroyclic derivatives useful for the treatment of diseases or conditions related to the central nervous system
(1R)-1-[1-(3,4-dichlorophenyl)cyclobutyl]-N-(4-ethoxybutyl)-3-methylbutan-1-amine	KI	1.16 nM	US-10035761: Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives
9-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-1,4,9-triazaspiro[5.5]undecane	IC50	1.32 nM	US-9908897: Spirocyclic derivatives
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine	KI	1.4 nM
4-[[4-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutyl]amino]butanamide	KI	1.5 nM	US-9096515: Methods of using cycloalkylmethylamine derivatives
4-[[1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutyl]amino]butanamide	KI	1.5 nM	US-9296681: Cycloalkylmethylamines
4-(aminomethyl)-1-[3-fluoro-5-(3-fluorophenoxy)phenyl]piperidin-4-ol (E14)	IC50	1.51 nM	US-9920053: N-(hetero)aryl-substituted heteroyclic derivatives useful for the treatment of diseases or conditions related to the central nervous system
MOLI000038	KI	1.53 nM
4-(3,4-dichlorophenyl)-1,1-dimethyl-7-pyrazin-2-yl-3,4-dihydro-2H-isoquinoline	IC50	1.8 nM	US-9034899: Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
3-[(cyclopropylamino)methyl]-1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3-ol (E30)	IC50	1.91 nM	US-9920053: N-(hetero)aryl-substituted heteroyclic derivatives useful for the treatment of diseases or conditions related to the central nervous system
(1R,2S,3R,5R)-methyl 3-(4-iodophenyl)-8-aza-bicyclo[3.2.1]octane-2-carboxylate	KI	1.98 nM
4-(3,4-dichlorophenyl)-1,1-dimethyl-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-3,4-dihydro-2H-isoquinoline	IC50	2.1 nM	US-9034899: Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
1-[1-(3,4-dichlorophenyl)cyclobutyl]-N-(2-ethoxyethyl)-3-methylbutan-1-amine	KI	2.38 nM	US-10035761: Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives
(1R)-1-[1-(3,4-dichlorophenyl)cyclobutyl]-N-(4-methoxybutyl)-3-methylbutan-1-amine	KI	2.39 nM	US-10035761: Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives
6-[4-(3,4-dichlorophenyl)-1,1-dimethyl-3,4-dihydro-2H-isoquinolin-7-yl]pyridazin-3-amine	IC50	2.4 nM	US-9034899: Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
2-(3-fluorophenoxy)-6-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyridine-4-carbonitrile	IC50	2.45 nM	US-9908897: Spirocyclic derivatives
(6R)-2-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-2,8-diazaspiro[4.5]decan-6-ol	IC50	2.57 nM	US-9908897: Spirocyclic derivatives
3-(4-bromo-phenyl)-5-methylene-7-aza-tricyclo[5.3.0.04,8]decane	KI	2.94 nM
(S)-mianserin	KI	3 nM
4-(1-benzothiophen-5-yl)-2-methyl-3,4-dihydro-1H-isoquinoline	KI	3.8 nM	US-9085531: Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
4-(1H-indol-5-yl)-2-methyl-3,4-dihydro-1H-isoquinoline	KI	3.8 nM	US-9085531: Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
9-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane	IC50	3.8 nM	US-9908897: Spirocyclic derivatives
S18616	KI	3.98 nM
{4-amino-1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methanol (E20)	IC50	4.07 nM	US-9920053: N-(hetero)aryl-substituted heteroyclic derivatives useful for the treatment of diseases or conditions related to the central nervous system
9-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-1-methyl-1,4,9-triazaspiro[5.5]undecane	IC50	4.17 nM	US-9908897: Spirocyclic derivatives
(R)-3-(2-Ethoxypyridin-3-yloxy)-N-methyl-3-phenylpropan-1-amine	KI	4.2 nM	US-10188758: Organic compounds
1-[4-(1-benzothiophen-5-yl)-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl]-N,N-dimethylmethanamine	KI	4.4 nM	US-9085531: Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
4-(1-benzofuran-7-yl)-2-methyl-3,4-dihydro-1H-isoquinoline	KI	4.5 nM	US-9085531: Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
4-(1-benzofuran-5-yl)-2-methyl-3,4-dihydro-1H-isoquinoline	KI	4.5 nM	US-9085531: Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
BDBM50054534	KI	4.5 nM	US-9085531: Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
9-[2,6-difluoro-3-(3-fluorophenoxy)phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane	IC50	4.79 nM	US-9908897: Spirocyclic derivatives
(1R,2S,3R,5R)-methyl 3-p-tolyl-8-aza-bicyclo[3.2.1]octane-2-carboxylate	KI	4.88 nM
3-[1-(3,4-dichlorophenyl)-9-azatricyclo[7.2.2.02,7]trideca-2(7),3,5-trien-5-yl]-1H-pyridazin-6-one	IC50	5.1 nM	US-9045468: 2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
(2S,3R)-methyl 3-(4-chlorophenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carboxylate	IC50	5.14 nM
(1R)-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methyl-N-(3-propoxypropyl)butan-1-amine	KI	5.45 nM	US-10035761: Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives
3-[4-(2,2-Dibromo-vinyl)-phenyl]-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester	KI	5.6 nM
N-({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-3-hydroxypyrrolidin-3-yl}methyl)azetidine-3-carboxamide (E35)	IC50	5.62 nM	US-9920053: N-(hetero)aryl-substituted heteroyclic derivatives useful for the treatment of diseases or conditions related to the central nervous system
9-[4-(3,5-difluorophenoxy)-6-methylpyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane	IC50	5.75 nM	US-9908897: Spirocyclic derivatives
4-[4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]benzamide	IC50	5.8 nM	US-9034899: Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
1-(3,4-dichlorophenyl)-5-(6-methoxypyridazin-3-yl)-9-azatricyclo[7.2.2.02,7]trideca-2(7),3,5-triene	IC50	5.9 nM	US-9045468: 2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
3-(2-methoxyphenoxy)-N-methyl-3-phenylpropan-1-amine	KI	6 nM
2-[(1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]-5-(4-nitrophenyl)-1,3-thiazole	KI	6.1 nM
4-(aminomethyl)-1-[2-fluoro-3-(3-fluorophenoxy)phenyl]piperidin-4-ol (E17)	IC50	6.76 nM	US-9920053: N-(hetero)aryl-substituted heteroyclic derivatives useful for the treatment of diseases or conditions related to the central nervous system
3-(3-fluorophenoxy)-2-methyl-5-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)benzonitrile	IC50	6.92 nM	US-9908897: Spirocyclic derivatives
2-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-2,9-diazaspiro[4.5]decan-6-one	IC50	7.08 nM	US-9908897: Spirocyclic derivatives
6-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine	IC50	7.1 nM	US-9034899: Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof

ChEMBL bioactivities

5117 potent at pChembl≥5 of 5447 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.19	IC50	0.065	nM	CHEMBL3819243
10.10	IC50	0.08	nM	CHEMBL3818117
10.10	IC50	0.079	nM	CHEMBL3819201
10.10	Ki	0.07943	nM	CHEMBL4228464
10.00	IC50	0.1	nM	CHEMBL3817915
9.90	Ki	0.1259	nM	CHEMBL597000
9.89	IC50	0.13	nM	CHEMBL3818953
9.80	Ki	0.1585	nM	CHEMBL596987
9.80	IC50	0.1585	nM	CHEMBL608151
9.68	IC50	0.21	nM	CHEMBL3818901
9.60	Ki	0.2512	nM	CHEMBL605209
9.60	IC50	0.2512	nM	CHEMBL597000
9.52	Ki	0.3	nM	CHEMBL179249
9.52	Ki	0.3	nM	ESREBOXETINE
9.50	IC50	0.3162	nM	CHEMBL2338048
9.50	Ki	0.3162	nM	CHEMBL597000
9.48	IC50	0.33	nM	CHEMBL3593400
9.48	IC50	0.33	nM	CHEMBL4791288
9.40	IC50	0.3981	nM	CHEMBL2337605
9.40	IC50	0.3981	nM	CHEMBL2337586
9.40	Ki	0.3981	nM	CHEMBL602235
9.40	IC50	0.3981	nM	CHEMBL2021580
9.40	Ki	0.3981	nM	CHEMBL1818444
9.40	Ki	0.3981	nM	CHEMBL1818445
9.30	IC50	0.5012	nM	CHEMBL2338049
9.30	IC50	0.5012	nM	CHEMBL2338042
9.30	IC50	0.5012	nM	CHEMBL2338036
9.30	IC50	0.5012	nM	CHEMBL2337601
9.30	IC50	0.5012	nM	CHEMBL2337595
9.30	Ki	0.5	nM	CHEMBL4227444
9.30	Ki	0.5012	nM	CHEMBL611063
9.30	Ki	0.5012	nM	CHEMBL608151
9.30	Ki	0.5012	nM	CHEMBL599845
9.30	Ki	0.5012	nM	CHEMBL1224320
9.30	IC50	0.5	nM	CHEMBL1812750
9.22	IC50	0.6	nM	CHEMBL4750411
9.22	Ki	0.6	nM	DESIPRAMINE
9.21	IC50	0.62	nM	CHEMBL544370
9.20	IC50	0.631	nM	CHEMBL2338044
9.20	Ki	0.631	nM	CHEMBL598215
9.20	Ki	0.631	nM	CHEMBL598825
9.20	Ki	0.631	nM	CHEMBL610795
9.20	Ki	0.631	nM	CHEMBL1224240
9.20	Ki	0.631	nM	CHEMBL1818448
9.19	IC50	0.64	nM	CHEMBL3818471
9.15	Ki	0.7	nM	CHEMBL5886852
9.12	Ki	0.76	nM	CHEMBL181188
9.11	IC50	0.77	nM	CHEMBL3593399
9.10	IC50	0.7943	nM	CHEMBL2338052
9.10	IC50	0.7943	nM	CHEMBL2338045

PubChem BioAssay actives

3154 with measured affinity, of 6100 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
2-[[(1R,5S,6S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-4-methyl-1,3-thiazole	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0001	uM
(1S,4R,5S)-5-(3,4-dichlorophenyl)-4-(methoxymethyl)-2-azabicyclo[3.2.1]octane	1388123: Binding affinity to human NET	ki	0.0001	uM
(1S,5S,6S)-1-(3,4-dichlorophenyl)-6-(ethoxymethyl)-3-azabicyclo[3.1.0]hexane	462704: Inhibition of [3H]noradrenalin reuptake at human NET expressed in LLCPK cells by scintillation proximity assay	ic50	0.0002	uM
(1S,5S,6S)-6-(cyclopentyloxymethyl)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0002	uM
(2S)-2-[(S)-(2-methylphenyl)sulfanyl-phenylmethyl]morpholine	412245: Displacement of [3H]nisoxetine from human NET receptor expressed in HEK293 cells	ki	0.0003	uM
(E)-but-2-enedioic acid;N-[[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl]acetamide	1234512: Inhibition of human NET expressed in CHOK1 cells incubated for 45 mins by [3H]-norepinephrine uptake assay	ic50	0.0003	uM
N-[[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl]acetamide;hydrochloride	1712186: Inhibition of human NET expressed in CHO-K1 cells assessed as inhibition of [3H]-norepinephrine reuptake measured after 45 mins by Microscintillation counting analysis	ic50	0.0003	uM
(1R,5R,6R)-1-(3,4-dichlorophenyl)-6-(propan-2-yloxymethyl)-3-azabicyclo[3.1.0]hexane	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0003	uM
(1S,5S,6S)-1-(3,4-dichlorophenyl)-6-(propan-2-yloxymethyl)-3-azabicyclo[3.1.0]hexane	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0004	uM
methyl (1R,2S,3R,5S)-3-(3-fluoro-4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate	610458: Inhibition of human NET expressed in HEK293 cells assessed as inhibition of [3H]NE reuptake after 10 mins by scintillation counting	ic50	0.0005	uM
(3R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)-phenylmethyl]pyrrolidine	731055: Inhibition of human recombinant NET expressed in HEK293 cells assessed as inhibition of [3H]NE reuptake	ic50	0.0005	uM
(1S,5S,6S)-1-(3,4-dichlorophenyl)-6-(propoxymethyl)-3-azabicyclo[3.1.0]hexane	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0005	uM
(1S,5S,6S)-6-(cyclobutyloxymethyl)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane;hydrochloride	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0005	uM
(7-fluoro-1H-indol-5-yl)-[3-(3-methylbutyl)pyrrolidin-3-yl]methanone	502243: Inhibition of [3H]norepinephrine reuptake at norepinephrine transporter	ki	0.0005	uM
6-(1,3-benzodioxol-5-yl)-3,4-dihydro-2H-pyrimido[1,2-b]isoindol-6-ol;hydrochloride	147756: Inhibition of NE uptake in HEK cells expressing human noradrenaline transporter (hNET)	ic50	0.0006	uM
9-methyl-6-[3-[(1S)-3-(methylamino)-1-thiophen-2-ylpropoxy]phenyl]-2-methylsulfanyl-7,8-dihydropyrimido[4,5-e][1,4]diazepin-5-one	1709035: Inhibition of human NET expressed in HEK293 cells assessed as reduction in ASP+ uptake incubated for 20 mins before ASP+ addition and measured after 90 mins by scintillation counting method	ic50	0.0006	uM
(1R,5R,6R)-1-(3,4-dichlorophenyl)-6-(propoxymethyl)-3-azabicyclo[3.1.0]hexane	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0006	uM
(1R,5R,6R)-6-(methoxymethyl)-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0006	uM
Desipramine	1799301: Radioligand Binding Assay (Ki) from Article 10.1016/j.bmc.2009.09.023: “Dual acting norepinephrine reuptake inhibitors and 5-HT(2A) receptor antagonists: Identification, synthesis and activity of novel 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles.”	ki	0.0006	uM
(1R,5R,6R)-6-(cyclopropylmethoxymethyl)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0006	uM
[3-(3,3-dimethylbutyl)pyrrolidin-3-yl]-(5-methylquinolin-2-yl)methanone	502243: Inhibition of [3H]norepinephrine reuptake at norepinephrine transporter	ki	0.0006	uM
(2S)-2-[(S)-(2-methoxyphenyl)sulfanyl-phenylmethyl]morpholine	318296: Displacement of [3H]nisoxetine from human NET expressed in HEK293 cells	ki	0.0008	uM
2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide	731055: Inhibition of human recombinant NET expressed in HEK293 cells assessed as inhibition of [3H]NE reuptake	ic50	0.0008	uM
methyl (3S,5R)-3-(4-chloro-3-methylphenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate	147722: Inhibition of Norepinephrine (NA) reuptake using cloned human Norepinephrine transporter was determined	ic50	0.0008	uM
(3S)-3-[(R)-(2,6-dichloro-3,5-difluorophenoxy)-phenylmethyl]pyrrolidine	731055: Inhibition of human recombinant NET expressed in HEK293 cells assessed as inhibition of [3H]NE reuptake	ic50	0.0008	uM
5-(4-chlorophenyl)-9-fluoro-2,3-dihydroimidazo[1,2-b]isoindol-5-ol	147760: Displacement of [125I]RTI-55 from human Norepinephrine transporter expressed in HEK cells	ki	0.0009	uM
(2S)-2-[(S)-(2-methoxyphenoxy)-phenylmethyl]morpholine	318296: Displacement of [3H]nisoxetine from human NET expressed in HEK293 cells	ki	0.0009	uM
5-(4-chlorophenyl)-2,3-dihydroimidazo[1,2-b]isoindol-5-ol	1443747: Inhibition of recombinant human NET expressed in HEK293 cell membranes assessed as reduction in [3H]-norepinephrine uptake incubated for 22 mins by micro beta scintillation counting analysis	ic50	0.0009	uM
methyl (1R,2S,3S,5S)-3-(4-chloro-3-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate	610458: Inhibition of human NET expressed in HEK293 cells assessed as inhibition of [3H]NE reuptake after 10 mins by scintillation counting	ic50	0.0009	uM
3-[1-[[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl]-2-oxo-3-pyridinyl]-4H-1,2,4-oxadiazol-5-one;hydrochloride	1309227: Inhibition of human NET expressed in CHO cells assessed as [3H]-Norepinephrine reuptake incubated for 45 mins measured after 30 mins by topcount method	ic50	0.0010	uM
3-[3-(2-fluorophenyl)-2,2-dioxo-2lambda6,1,3-benzothiadiazol-1-yl]-N-methylpropan-1-amine	483451: Inhibition of human NET-mediated norepinephrine uptake in MDCK-Net6 cells	ic50	0.0010	uM
(2S)-2-[(S)-(2-methylphenoxy)-phenylmethyl]morpholine	412245: Displacement of [3H]nisoxetine from human NET receptor expressed in HEK293 cells	ki	0.0010	uM
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxo-2lambda6,1,3-benzothiadiazol-1-yl]-1-(methylamino)butan-2-ol	483451: Inhibition of human NET-mediated norepinephrine uptake in MDCK-Net6 cells	ic50	0.0010	uM
5-(3-benzylpyrrolidin-3-yl)-1H-indole	345387: Inhibition of NET	ki	0.0010	uM
5-(3-benzylpyrrolidin-3-yl)-1-methylindole	345387: Inhibition of NET	ki	0.0010	uM
6-(3-benzylpyrrolidin-3-yl)-1H-indole	345387: Inhibition of NET	ki	0.0010	uM
(2S)-2-[(S)-[2-(2-fluoroethoxy)phenyl]sulfanyl-phenylmethyl]morpholine	318296: Displacement of [3H]nisoxetine from human NET expressed in HEK293 cells	ki	0.0010	uM
(1S,5S,6S)-6-(methoxymethyl)-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0010	uM
4-[4,5-difluoro-2-(4-fluorophenoxy)phenyl]piperidine	438205: Displacement of [125I]RTI-55 from human NET expressed in HEK293 cells	ki	0.0010	uM
(1S,6S)-6-(3,4-dichlorophenyl)-1-(1-methoxybut-3-enyl)-3-azabicyclo[4.1.0]heptane	491801: Displacement of [N-methyl-3H]nisoxetine from human recombinant NET expressed in pig LLCPK cells after 2 hrs by liquid scintillation counting	ki	0.0010	uM
(3-butylpyrrolidin-3-yl)-(7-fluoro-1H-indol-5-yl)methanone	502243: Inhibition of [3H]norepinephrine reuptake at norepinephrine transporter	ki	0.0010	uM
4-[3-(2-fluorophenyl)-2,2-dioxo-2lambda6,1,3-benzothiadiazol-1-yl]-N-methylbutan-1-amine	483452: Displacement of [3H]nisoxetine from human NET expressed in MDCK-Net6 cells	ic50	0.0011	uM
2-[(2-ethoxyphenoxy)-phenylmethyl]morpholine	147725: In vitro binding affinity against human norepinephrine transporter in human embryonic kidney cell line by using [3H]-nisoxatine radioligand	ki	0.0011	uM
Protriptyline	255303: Percent inhibition against Norepinephrine transporter at 1 uM nonselective	ic50	0.0011	uM
(1S,2S)-3-(methylamino)-2-naphthalen-2-yl-1-phenylpropan-1-ol	1388132: Binding affinity to human NET expressed in HEK293 cells after 60 mins in presence of [3H]imipramine by liquid scintillation counting	ki	0.0012	uM
(2S)-2-[(S)-[2-(3-fluoropropoxy)phenyl]sulfanyl-phenylmethyl]morpholine	318296: Displacement of [3H]nisoxetine from human NET expressed in HEK293 cells	ki	0.0012	uM
N-methyl-1-[(1S,2S)-2-naphthalen-1-yloxy-2-thiophen-2-ylcyclopropyl]methanamine;hydrochloride	431485: Inhibition of [3H]norepinephrine reuptake at norepinephrine transporter	ki	0.0012	uM
(1S,5S,6S)-6-(cyclobutyloxymethyl)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane	462682: Displacement of [3H]nisoxetine from human recombinant NET expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0013	uM
methyl 2-[(S)-[(2S)-morpholin-2-yl]-phenylmethoxy]benzoate	318296: Displacement of [3H]nisoxetine from human NET expressed in HEK293 cells	ki	0.0013	uM
[3-(3,3-dimethylbutyl)pyrrolidin-3-yl]-(7-fluoro-1H-indol-5-yl)methanone	502243: Inhibition of [3H]norepinephrine reuptake at norepinephrine transporter	ki	0.0013	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cocaine	decreases reaction, increases import, decreases activity, increases expression	4
Norepinephrine	decreases reaction, decreases activity, decreases expression, increases uptake, affects binding (+3 more)	4
N-Methyl-3,4-methylenedioxyamphetamine	decreases reaction, increases import, increases uptake, decreases activity, affects response to substance	4
Amphetamine	affects response to substance, affects binding, decreases reaction, increases import, decreases activity (+1 more)	3
para-methyl-4-methylaminorex	decreases reaction, increases reaction, increases uptake, affects binding, decreases activity	2
Dextroamphetamine	decreases activity, affects response to substance	2
Nickel	decreases expression	2
1-Methyl-4-phenylpyridinium	affects expression, decreases reaction, increases reaction, increases uptake	2
4-methylaminorex	decreases activity, increases uptake	1
1-phenyl-2-(1-pyrrolidinyl)-1-pentanone	decreases reaction, increases import	1
2-(4-bromo-2,5-dimethoxyphenyl)-N-((2-methoxyphenyl)methyl)ethanamine	decreases reaction, increases import	1
5-(2-aminopropyl)benzofuran	decreases reaction, increases import	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects cotreatment, increases methylation	1
nisoxetine	affects binding, decreases reaction	1
terbufos	increases methylation	1
sodium arsenite	decreases expression	1
phenethylamine	increases activity, increases reaction	1
tryptamine	decreases reaction, increases activity, increases reaction	1
4-fluoroamphetamine	decreases reaction, increases import	1
4-methoxymethamphetamine	decreases reaction, increases import	1
2-(4-bromo-2,5-dimethoxyphenyl)ethylamine	decreases reaction, increases import	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	affects methylation	1
indatraline	decreases reaction, increases activity, increases reaction	1
belinostat	increases expression	1
2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine	decreases reaction, increases import	1
1-(2-fluorophenyl)-3-(2-(morpholin-2-yl)ethyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide	affects binding, decreases activity	1
2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone	decreases reaction, increases import	1
Resveratrol	affects cotreatment, decreases expression	1

ChEMBL screening assays

929 unique, capped per target: 885 binding, 25 admet, 15 functional, 3 toxicity, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL750367	Binding	selectivity ratio between noradrenaline and dopamine transporter binding	Design, synthesis, and biological evaluation of novel non-piperazine analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines as dopamine transporter inhibitors. — J Med Chem
CHEMBL1069371	Functional	Agonist activity at NET	Design, synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists. — Bioorg Med Chem Lett
CHEMBL1737998	Unclassified	PUBCHEM_BIOASSAY: Late-stage radioligand binding dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): PDSP screen Ki. (Class of assay: screening) [Related pubchem assays (depositor defined):AID1792, AID1796, AID1823, AID253	PubChem BioAssay data set

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E7VM	293-hNET	Transformed cell line	Female
CVCL_F1X3	ValiScreen human SLC6A2	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02171988	PHASE4	COMPLETED	Effect of Medical Treatment and Prognosis of Postural Orthostatic Tachycardia Syndrome (POTS)
NCT05363514	PHASE4	NOT_YET_RECRUITING	Low Dose Naltrexone Use in Patients With POTS
NCT05481177	PHASE4	UNKNOWN	Ivabradine for Long-Term Effects of COVID-19 With POTS Cohort
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT03182725	PHASE3	COMPLETED	Effect of Ivabradine on Patients With Postural Orthostatic Tachycardia Syndrome
NCT03365414	PHASE3	WITHDRAWN	A Study to Systematically Assess the Efficacy and Safety of Intravenous Albumin Infusions in Severe POTS
NCT00517959	PHASE3	UNKNOWN	SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors
NCT01096368	PHASE3	COMPLETED	Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma
NCT00865917	PHASE2	UNKNOWN	Cardiovascular Effects of Selective I(f)-Channel Blockade
NCT03674541	PHASE2	COMPLETED	The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
NCT04855266	PHASE2	WITHDRAWN	Iron Sucrose in Patients With Iron Deficiency and POTS
NCT05633407	PHASE2	COMPLETED	Efficacy and Safety Study of Efgartigimod in Adults With Post-COVID-19 POTS
NCT06133075	PHASE2	COMPLETED	Using Mirabegron to Increase BP in Patients With POTS
NCT06593600	PHASE2	ACTIVE_NOT_RECRUITING	Study of Natriuretic Peptide Receptor 1 (NPR1) Antagonist in Adult Patients With Postural Orthostatic Tachycardia Syndrome (POTS)
NCT07585513	PHASE2	NOT_YET_RECRUITING	Beta-3 Enhanced Autonomic Therapy for POTS
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00003479	PHASE2	TERMINATED	Antineoplaston Therapy in Treating Patients With Ependymoma
NCT00520936	PHASE2	COMPLETED	A Study of Pemetrexed in Children With Recurrent Cancer
NCT00840047	PHASE2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT01088035	PHASE2	TERMINATED	Carboplatin as a Radiosensitizer in Treating Childhood Ependymoma
NCT01247922	PHASE2	TERMINATED	Single-agent Erlotinib in Patients Previously Treated With Oral Etoposide in Protocol OSI-774-205
NCT01288235	PHASE2	COMPLETED	Proton Radiotherapy for Pediatric Brain Tumors Requiring Partial Brain Irradiation
NCT01295944	PHASE2	COMPLETED	Carboplatin and Bevacizumab for Recurrent Ependymoma
NCT01356290	PHASE2	RECRUITING	Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors
NCT01836549	PHASE2	TERMINATED	Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
NCT02125786	PHASE2	ACTIVE_NOT_RECRUITING	A Trial of Surgery and Fractionated Re-Irradiation for Recurrent Ependymoma
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT03095248	PHASE2	TERMINATED	Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03173950	PHASE2	COMPLETED	Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers
NCT03194906	PHASE2	COMPLETED	Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)