Synonym
NS8593; NS 8593; NS-8593; NS8593 HCl; NS8593HCl.
IUPAC/Chemical Name
N-[(1R)-1,2,3,4-Tetrahydro-1-naphthalenyl]-1H-benzimidazol-2-amine hydrochloride
InChi Key
VWEKCDTXUUPBNA-PFEQFJNWSA-N
InChi Code
InChI=1S/C17H17N3.ClH/c1-2-8-13-12(6-1)7-5-11-14(13)18-17-19-15-9-3-4-10-16(15)20-17;/h1-4,6,8-10,14H,5,7,11H2,(H2,18,19,20);1H/t14-;/m1./s1
SMILES Code
[H]Cl.C1(N[C@@H]2CCCC3=C2C=CC=C3)=NC4=CC=CC=C4N1
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
NS8593 hydrochloride reversibly inhibits SK3-mediated currents with a Kd value of 77 nM, inhibits all the SK1-3 subtypes Ca2+-dependently (Kds of 0.42, 0.60, and 0.73 μM, respectively, at 0.5 μM Ca2+), and does not affect the Ca2+-activated K+ channels of intermediate and large conductance (hIK and hBK channels, respectively).
In vitro activity:
To unravel the mechanism by which the channel TRPM7 blockade inhibits MRTF-A and resultant target gene expression, the RhoA activation status in HuH7 cells treated with NS8593 was first assessed. By immunoprecipitation with an antibody specifically recognizing GTP-loaded RhoA, it was found that the amount of GTP-loaded RhoA was reduced by more than 50% in HuH7 cells treated with NS8593, whereas total RhoA levels were unaltered. Likewise, the downstream effector of RhoA, ROCK2, was downregulated upon TRPM7 blockade. Treatment with the TRPM7 channel blocker NS8593 also resulted in a pronounced decrease in the mean cellular F-actin content. Immunofluorescence analysis using a fluorescent phalloidin conjugate showed that stress fibers, particularly in the nuclear and perinuclear region, were strongly reduced and reorganized in cortical actin networks upon treatment with NS8593.
Reference: Oncogene. 2020 Mar;39(11):2328-2344. https://pubmed.ncbi.nlm.nih.gov/31844251/
In vivo activity:
In rat, guinea pig, and rabbit ex vivo and in vivo models of atrial fibrillation (AF), 3 different SK channel inhibitors, UCL1684, N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA), and NS8593, were used to assess the hypothesis that pharmacological inhibition of SK channels is antiarrhythmic. In an in vivo rat model of acute AF induced by burst pacing, injection of 5 mg/kg of either NS8593 or amiodarone shortened AF duration significantly to (23.2+/-20.0%, P<0.001, n=5, and 26.2+/-17.9%, P<0.001, n=5, respectively) as compared with injection of vehicle (96.3+/-33.2%, n=5). In conclusion, inhibition of SK channels prolongs atrial effective refractory period without affecting QT interval and prevents and terminates AF ex vivo and in vivo, thus offering a promising new therapeutic opportunity in the treatment of AF.
Reference: Circ Arrhythm Electrophysiol. 2010 Aug;3(4):380-90. https://pubmed.ncbi.nlm.nih.gov/20562443/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
56.7 |
188.98 |
|
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
299.80
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Sørensen US, Strøbaek D, Christophersen P, Hougaard C, Jensen ML, Nielsen EØ, Peters D, Teuber L. Synthesis and structure-activity relationship studies of 2-(N-substituted)-aminobenzimidazoles as potent negative gating modulators ofsmall conductance Ca2+-activated K+ channels. J Med Chem. 2008 Dec 11;51(23):7625-34. doi: 10.1021/jm800809f. PMID: 18998663.
2. Voringer S, Schreyer L, Nadolni W, Meier MA, Woerther K, Mittermeier C, Ferioli S, Singer S, Holzer K, Zierler S, Chubanov V, Liebl B, Gudermann T, Muehlich S. Inhibition of TRPM7 blocks MRTF/SRF-dependent transcriptional and tumorigenic activity. Oncogene. 2020 Mar;39(11):2328-2344. doi: 10.1038/s41388-019-1140-8. Epub 2019 Dec 16. PMID: 31844251.
3. Diness JG, Sørensen US, Nissen JD, Al-Shahib B, Jespersen T, Grunnet M, Hansen RS. Inhibition of small-conductance Ca2+-activated K+ channels terminates and protects against atrial fibrillation. Circ Arrhythm Electrophysiol. 2010 Aug;3(4):380-90. doi: 10.1161/CIRCEP.110.957407. Epub 2010 Jun 19. PMID: 20562443.
4. Haugaard MM, Hesselkilde EZ, Pehrson S, Carstensen H, Flethøj M, Præstegaard KF, Sørensen US, Diness JG, Grunnet M, Buhl R, Jespersen T. Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses. Heart Rhythm. 2015 Apr;12(4):825-35. doi: 10.1016/j.hrthm.2014.12.028. Epub 2014 Dec 24. PMID: 25542425.
In vitro protocol:
1. Sørensen US, Strøbaek D, Christophersen P, Hougaard C, Jensen ML, Nielsen EØ, Peters D, Teuber L. Synthesis and structure-activity relationship studies of 2-(N-substituted)-aminobenzimidazoles as potent negative gating modulators ofsmall conductance Ca2+-activated K+ channels. J Med Chem. 2008 Dec 11;51(23):7625-34. doi: 10.1021/jm800809f. PMID: 18998663.
2. Voringer S, Schreyer L, Nadolni W, Meier MA, Woerther K, Mittermeier C, Ferioli S, Singer S, Holzer K, Zierler S, Chubanov V, Liebl B, Gudermann T, Muehlich S. Inhibition of TRPM7 blocks MRTF/SRF-dependent transcriptional and tumorigenic activity. Oncogene. 2020 Mar;39(11):2328-2344. doi: 10.1038/s41388-019-1140-8. Epub 2019 Dec 16. PMID: 31844251.
In vivo protocol:
1.Diness JG, Sørensen US, Nissen JD, Al-Shahib B, Jespersen T, Grunnet M, Hansen RS. Inhibition of small-conductance Ca2+-activated K+ channels terminates and protects against atrial fibrillation. Circ Arrhythm Electrophysiol. 2010 Aug;3(4):380-90. doi: 10.1161/CIRCEP.110.957407. Epub 2010 Jun 19. PMID: 20562443.
2. Haugaard MM, Hesselkilde EZ, Pehrson S, Carstensen H, Flethøj M, Præstegaard KF, Sørensen US, Diness JG, Grunnet M, Buhl R, Jespersen T. Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses. Heart Rhythm. 2015 Apr;12(4):825-35. doi: 10.1016/j.hrthm.2014.12.028. Epub 2014 Dec 24. PMID: 25542425.
1: Haugaard MM, Hesselkilde EZ, Pehrson S, Carstensen H, Flethøj M, Præstegaard KF, Sørensen US, Diness JG, Grunnet M, Buhl R, Jespersen T. Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses. Heart Rhythm. 2015 Apr;12(4):825-35. doi: 10.1016/j.hrthm.2014.12.028. Epub 2014 Dec 24. PubMed PMID: 25542425.
2: Jenkins DP, Strøbæk D, Hougaard C, Jensen ML, Hummel R, Sørensen US, Christophersen P, Wulff H. Negative gating modulation by (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine (NS8593) depends on residues in the inner pore vestibule: pharmacological evidence of deep-pore gating of K(Ca)2 channels. Mol Pharmacol. 2011 Jun;79(6):899-909. doi: 10.1124/mol.110.069807. Epub 2011 Mar 1. PubMed PMID: 21363929; PubMed Central PMCID: PMC3102549.
3: Strøbaek D, Hougaard C, Johansen TH, Sørensen US, Nielsen EØ, Nielsen KS, Taylor RD, Pedarzani P, Christophersen P. Inhibitory gating modulation of small conductance Ca2+-activated K+ channels by the synthetic compound (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) reduces afterhyperpolarizing current in hippocampal CA1 neurons. Mol Pharmacol. 2006 Nov;70(5):1771-82. Epub 2006 Aug 22. PubMed PMID: 16926279.
