NET | Monoamine transporter subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

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NET

Target not currently curated in GtoImmuPdb

Target id: 926

Nomenclature: NET

Systematic Nomenclature: SLC6A2

Family: Monoamine transporter subfamily

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 12 617 16q12.2 SLC6A2 solute carrier family 6 member 2
Mouse 12 617 8 44.99 cM Slc6a2 solute carrier family 6 (neurotransmitter transporter, noradrenalin), member 2
Rat - - 19p11 Slc6a2 solute carrier family 6 member 2
Previous and Unofficial Names
NAT1 | NET1 | SLC6A5 | NaCl-dependent norepinephrine transporter | norepinephrine transporter | sodium-dependent noradrenaline transporter | NE transporter | solute carrier family 6 (neurotransmitter transporter), member 2 | solute carrier family 6 (neurotransmitter transporter, noradrenalin), member 2 | solute carrier family 6 (neurotransmitter transporter
Database Links
Specialist databases
Bioparadigms SLC Tables SLC6A2 (Hs)
Other databases
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
UniProtKB
Wikipedia
Substrates and Reaction Kinetics
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
(-)-adrenaline Hs -
(-)-noradrenaline Hs -
dopamine Hs -
MPP+ Hs -
methamphetamine Hs -
amphetamine Hs -
Stoichiometry
1 noradrenaline: 1 Na+:1 Cl- [8]

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]mazindol Rn Inhibition 9.3 pKd 18
pKd 9.3 (Kd 5x10-10 M) [18]
protriptyline Hs Inhibition 8.9 pKd 21
pKd 8.9 (Kd 1.41x10-9 M) [21]
atomoxetine Hs Inhibition 8.7 pKd 5
pKd 8.7 (Kd 2.03x10-9 M) [5]
[3H]nisoxetine Hs Inhibition 8.4 pKd
pKd 8.4 (Kd 4x10-9 M)
clomipramine Hs Inhibition 7.4 pKd 21
pKd 7.4 (Kd 3.8x10-8 M) [21]
nefazodone Hs Inhibition 6.4 pKd 5
pKd 6.4 (Kd 3.6x10-7 M) [5]
Description: Dissociation constant of [3H]- nisoxatine vs. nefazodone.
mazindol Hs Inhibition 8.9 pKi
pKi 8.9 (Ki 1.26x10-9 M)
desipramine Hs Inhibition 8.7 pKi 16
pKi 8.7 (Ki 2.1x10-9 M) [16]
nisoxetine Hs Inhibition 8.4 pKi
pKi 8.4 (Ki 3.98x10-9 M)
lofepramine Hs Inhibition 8.3 pKi 21
pKi 8.3 (Ki 5.4x10-9 M) [21]
duloxetine Hs Inhibition 8.2 pKi 17
pKi 8.2 (Ki 5.97x10-9 M) [17]
nortriptyline Hs Inhibition 8.2 pKi 7
pKi 8.2 (Ki 6.3x10-9 M) [7]
protriptyline Hs Inhibition 8.2 pKi 13
pKi 8.2 (Ki 6.8x10-9 M) [13]
H05 Rn Inhibition 8.2 pKi 27
pKi 8.2 (Ki 6.72x10-9 M) [27]
nomifensine Hs Inhibition 8.1 pKi
pKi 8.1 (Ki 7.94x10-9 M)
reboxetine Hs Inhibition 8.0 pKi 26
pKi 8.0 (Ki 1x10-8 M) [26]
maprotiline Hs Inhibition 7.9 pKi 9
pKi 7.9 (Ki 1.2x10-8 M) [9]
N-desalkylquetiapine Hs Inhibition 7.9 pKi 10
pKi 7.9 (Ki 1.2x10-8 M) [10]
amoxapine Hs Inhibition 7.9 pKi 3
pKi 7.9 (Ki 1.3x10-8 M) [3]
imipramine Hs Inhibition 7.8 pKi
pKi 7.8 (Ki 1.6x10-8 M)
mianserin Rn Inhibition 7.6 pKi 14
pKi 7.6 (Ki 2.6x10-8 M) [14]
Description: Inhibition of [3H]NE uptake into rat synaptosomes
doxepin Hs Inhibition 7.5 pKi 3
pKi 7.5 (Ki 2.9x10-8 M) [3]
dosulepin Hs Inhibition 7.3 pKi 21
pKi 7.3 (Ki 4.6x10-8 M) [21]
ziprasidone Rn Inhibition 7.3 pKi 1
pKi 7.3 (Ki 4.8x10-8 M) [1]
dexamfetamine Hs Inhibition 7.0 pKi 2
pKi 7.0 (Ki 1.01x10-7 M) [2]
dexmethylphenidate Rn Inhibition 6.6 pKi 11
pKi 6.6 (Ki 2.7x10-7 M) [11]
Description: Displacement of [3H]nisoxetine from NET in Sprague-Dawley rat cortical tissue.
amitriptyline Hs Inhibition 6.5 pKi 2
pKi 6.5 (Ki 3.33x10-7 M) [2]
bupropion Hs Inhibition 6.4 pKi 12
pKi 6.4 (Ki 4.41x10-7 M) [12]
desvenlafaxine Hs Inhibition <6.2 pKi 6
pKi <6.2 (Ki >6.5x10-7 M) [6]
quetiapine Hs Inhibition 6.0 pKi 10
pKi 6.0 (Ki 9.27x10-7 M) [10]
trimipramine Hs Inhibition 5.6 pKi 21
pKi 5.6 (Ki 2.45x10-6 M) [21]
solriamfetol Hs Inhibition 5.4 pKi 4
pKi 5.4 (Ki 3.7x10-6 M) [4]
Description: In a radioligand binding assay using HEK293 cells expressing hNET.
sibutramine Hs Inhibition 5.3 pKi 3
pKi 5.3 (Ki 5.619x10-6 M) [3]
tapentadol Hs Inhibition 5.1 pKi 23
pKi 5.1 (Ki 8.8x10-6 M) [23]
phenelzine Hs Inhibition <5.0 pKi 21
pKi <5.0 (Ki >1x10-5 M) [21]
citalopram Hs Inhibition <3.0 pKi 28
pKi <3.0 (Ki >1x10-3 M) [28]
Description: Inhibition of [3H]dopamine uptake at human NET expressed in COS7 cells.
milnacipran Hs Inhibition 9.1 pIC50 24
pIC50 9.1 (IC50 7.94x10-10 M) [24]
protriptyline Hs Inhibition 8.8 pIC50 15
pIC50 8.8 (IC50 1.7x10-9 M) [15]
Description: Inhibition of [3H]nisoxetine binding to CHO cells expressing hNET.
norzotepine Hs Inhibition 8.0 pIC50 20
pIC50 8.0 (IC50 1.1x10-8 M) [20]
levomilnacipran Hs Inhibition 7.4 pIC50 25
pIC50 7.4 (IC50 4x10-8 M) [25]
methylphenidate Hs Inhibition 7.2 pIC50
pIC50 7.2 (IC50 6.1x10-8 M)
zotepine Hs Inhibition 7.2 pIC50 20
pIC50 7.2 (IC50 7.1x10-8 M) [20]
venlafaxine Hs Inhibition 6.3 pIC50 19
pIC50 6.3 (IC50 5.35x10-7 M) [19]
solriamfetol Hs Inhibition 5.4 pIC50 4
pIC50 5.4 (IC50 4.4x10-6 M) [4]
Description: In a NE reuptake assay in HEK293 cells expressing hNET.
View species-specific inhibitor tables
Inhibitor Comments
Protriptyline has also been shown to inhibit uptake of 5-HT in platelet rich human plasma [22].
Venlafaxine has a lower IC50 for SERT than for NET, therefore SERT has been tagged as the drug's primary target.
Clinically-Relevant Mutations and Pathophysiology
Disease:  Orthostatic intolerance
OMIM: 604715

References

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3. Auerbach SS, DrugMatrix® and ToxFX® Coordinator National Toxicology Program. National Toxicology Program: Dept of Health and Human Services. Accessed on 02/05/2014. Modified on 02/05/2014. DrugMatrix, https://ntp.niehs.nih.gov/drugmatrix/index.html

4. Baladi MG, Forster MJ, Gatch MB, Mailman RB, Hyman DL, Carter LP, Janowsky A. (2018) Characterization of the Neurochemical and Behavioral Effects of Solriamfetol (JZP-110), a Selective Dopamine and Norepinephrine Reuptake Inhibitor. J. Pharmacol. Exp. Ther., 366 (2): 367-376. [PMID:29891587]

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10. Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL. (2008) N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity. Neuropsychopharmacology, 33 (10): 2303-12. [PMID:18059438]

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13. Liu H, Altenbach RJ, Carr TL, Chandran P, Hsieh GC, Lewis LG, Manelli AM, Milicic I, Marsh KC, Miller TR et al.. (2008) cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia. J. Med. Chem., 51 (22): 7094-8. [PMID:18983139]

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20. Shobo M, Kondo Y, Yamada H, Mihara T, Yamamoto N, Katsuoka M, Harada K, Ni K, Matsuoka N. (2010) Norzotepine, a major metabolite of zotepine, exerts atypical antipsychotic-like and antidepressant-like actions through its potent inhibition of norepinephrine reuptake. J. Pharmacol. Exp. Ther., 333 (3): 772-81. [PMID:20223878]

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