E-4031 dihydrochloride

KV11.1 (hERG) channel blocker; inhibits rapid delayed rectifier K+ current (IKr) CAS# 113559-13-0

E-4031 dihydrochloride

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Quality Control of E-4031 dihydrochloride

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Chemical structure

E-4031 dihydrochloride

3D structure

Chemical Properties of E-4031 dihydrochloride

Cas No. 113559-13-0 SDF Download SDF
PubChem ID 3087190 Appearance Powder
Formula C21H29Cl2N3O3S M.Wt 474.44
Type of Compound N/A Storage Desiccate at -20°C
Solubility H2O : ≥ 50 mg/mL (105.39 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name N-[4-[1-[2-(6-methylpyridin-2-yl)ethyl]piperidine-4-carbonyl]phenyl]methanesulfonamide;dihydrochloride
SMILES CC1=NC(=CC=C1)CCN2CCC(CC2)C(=O)C3=CC=C(C=C3)NS(=O)(=O)C.Cl.Cl
Standard InChIKey ZQBNWMFBOSOOLX-UHFFFAOYSA-N
Standard InChI InChI=1S/C21H27N3O3S.2ClH/c1-16-4-3-5-19(22-16)12-15-24-13-10-18(11-14-24)21(25)17-6-8-20(9-7-17)23-28(2,26)27;;/h3-9,18,23H,10-15H2,1-2H3;2*1H
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of E-4031 dihydrochloride

DescriptionSelective blocker of KV11.1 (hERG) channels; inhibits the rapid delayed-rectifier K+ current (IKr). Reversibly prolongs action potential duration in guinea pig papillary muscle and isolated ventricular myocytes, without affecting Na+ or Ca2+ inward currents. Class III antiarrhythmic agent.

E-4031 dihydrochloride Dilution Calculator

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E-4031 dihydrochloride Molarity Calculator

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Preparing Stock Solutions of E-4031 dihydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1077 mL 10.5387 mL 21.0775 mL 42.155 mL 52.6937 mL
5 mM 0.4215 mL 2.1077 mL 4.2155 mL 8.431 mL 10.5387 mL
10 mM 0.2108 mL 1.0539 mL 2.1077 mL 4.2155 mL 5.2694 mL
50 mM 0.0422 mL 0.2108 mL 0.4215 mL 0.8431 mL 1.0539 mL
100 mM 0.0211 mL 0.1054 mL 0.2108 mL 0.4215 mL 0.5269 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on E-4031 dihydrochloride

E-4031 is a benzenesulfonamide antiarrhythmic agent; blocks the ATP-sensitive potassium channel. IC50 value: Target: K+ channel blocker in vitro: Dofetilide and E-4031 induced EADs or TdP in all assays (50-83%), and the induction correlated with a significant increase in beat-to-beat variability of repolarization [1]. E-4031 (0.1 mumol/L) significantly prolonged cycle length and action potential duration, depolarized maximum diastolic potential, and reduced both the upstroke velocity of the action potential and the diastolic depolarization rate [2]. in vivo: E-4031 in doses of 0.01 and 0.1 mg/kg that can provide the plasma concentrations effectively to inhibit IKrin vitro significantly delayed the repolarization beyond the initiation of diastole, resulting in the inversion of electro-mechanical coupling, which provides an ideal proarrhythmic substrate, while the durations of left ventricular systole and diastole remained the same [3]. Bepridil and E-4031 prolonged QT interval and ARI in all LV layers, though the magnitude of prolongation was greatest in Mid, increasing the transmural ARI dispersion, particularly during bradycardia [4].

References:
[1]. Nalos L, et al. Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes. Br J Pharmacol. 2012 Jan;165(2):467-78. [2]. Verheijck EE, et al. Effects of delayed rectifier current blockade by E-4031 on impulse generation in single sinoatrial nodal myocytes of the rabbit. Circ Res. 1995 Apr;76(4):607-15. [3]. Izumi-Nakaseko H, et al. Effects of selective IKr channel blockade by E-4031 on ventricular electro-mechanical relationship in the halothane-anesthetized dogs. Eur J Pharmacol. 2014 Oct 5;740:263-70. [4]. Izumi D, et al. Effects of bepridil versus E-4031 on transmural ventricular repolarization and inducibility of ventricular tachyarrhythmias in the dog. Pacing Clin Electrophysiol. 2010 Aug;33(8):950-9.

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References on E-4031 dihydrochloride

The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations.[Pubmed:11741928]

J Biol Chem. 2002 Feb 15;277(7):4989-98.

Mutations in the human ether-a-gogo-related gene (HERG) K(+) channel gene cause chromosome 7-linked long QT syndrome type 2 (LQT2), which is characterized by a prolonged QT interval in the electrocardiogram and an increased susceptibility to life-threatening cardiac arrhythmias. LQT2 mutations produce loss-of-function phenotypes and reduce I(Kr) currents either by the heteromeric assembly of non- or malfunctioning channel subunits with wild type subunits at the cell surface or by retention of misprocessed mutant HERG channels in the endoplasmic reticulum. Misprocessed mutations often encode for channel proteins that are functional upon incorporation into the plasma membrane. As a result the pharmacological correction of folding defects and restoration of protein function are of considerable interest. Here we report that the trafficking-deficient pore mutation HERG G601S was rescued by a series of HERG channel blockers that increased cell surface expression. Rescue by these pharmacological chaperones varied directly with their blocking potency. We used structure-activity relationships and site-directed mutagenesis to define the binding site of the pharmacological chaperones. We found that binding occurred in the inner cavity and correlated with hydrophobicity and cationic charge. Rescue was domain-restricted because the trafficking of two misprocessed mutations in the C terminus, HERG F805C and HERG R823W, was not restored by channel blockers. Our findings represent a first step toward the design of pharmacological chaperones that will rescue HERG K(+) channels without block.

Effects of delayed rectifier current blockade by E-4031 on impulse generation in single sinoatrial nodal myocytes of the rabbit.[Pubmed:7895335]

Circ Res. 1995 Apr;76(4):607-15.

The role of the delayed rectifier current (IK) in impulse generation was studied in single sinoatrial nodal myocytes of the rabbit. We used the class III antiarrhythmic drug E-4031, which blocks IK in rabbit ventricular myocytes. In single sinoatrial nodal cells, E-4031 (0.1 mumol/L) significantly prolonged cycle length and action potential duration, depolarized maximum diastolic potential, and reduced both the upstroke velocity of the action potential and the diastolic depolarization rate. Half of the cells were arrested completely. At higher concentrations (1 and 10 mumol/L), spontaneous activity ceased in all cells. Three ionic currents fundamental for pacemaking, ie, IK, the long-lasting inward calcium current (ICa,L), and the hyperpolarization-activated current (I(f)), were studied by using the whole-cell and amphotericin-perforated patch technique. E-4031 blocked part of the outward current during depolarizing steps as well as the tail current upon subsequent repolarization (ITD) in a dose-dependent manner. E-4031 (10 mumol/L) depressed ITD (88 +/- 4%) (n = 6), reduced peak ICa,L at 0 mV (29 +/- 15%) (n = 4), but did not affect I(f). Lower concentrations did not affect ICa,L. Additional use of 5 mumol/L nifedipine demonstrated that ITD is carried in part by a calcium-sensitive current. Interestingly, complete blockade of IK and ICa,L unmasked the presence of a background current component with a reversal potential of -32 +/- 5.4 mV (n = 8) and a conductance of 39.5 +/- 5.6 pS/pF, which therefore can contribute both to the initial part of repolarization and to full diastolic depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the new class III antiarrhythmic drug E-4031 on myocardial contractility and electrophysiological parameters.[Pubmed:1711611]

J Cardiovasc Pharmacol. 1991 Mar;17(3):480-7.

The effects of the new class III antiarrhythmic agent E-4031 were investigated in different guinea pig cardiac preparations. In left atria, E-4031 (10(-8)-10(-5) M) prolonged the functional refractory period up to 45% and reduced the frequency of spontaneously beating right atria by 32%. In papillary muscles, E-4031 (3 x 10(-8)-3 x 10(-7) M) reversibly prolonged the action potential duration (APD70) of fast and slow APs by 68 and 51%, respectively. Vmax, resting potential, and AP amplitude (APA) were not altered. In isolated ventricular myocytes, E-4031 reversibly prolonged the APD90 from 275 ms (control) to 1,496 ms (10(-6) M), pD2 value 6.5. The current changes that underlie the AP-prolonging effect were also studied in ventricular myocytes: in concentrations up to 10(-5) M), E-4031 did not affect the Na+ or Ca2+ inward current but reduced the delayed rectifier (IK) tail current by 76% (10(-7) M). Contractility was enhanced by E-4031 in isolated atria by 20% (3 x 10(-7) M) and increased cell shortening in ventricular myocytes. Thus, the class III antiarrhythmic action of E-4031 is due to a selective reduction of outward currents.

Description

E-4031 is a class III antiarrhythmic agent which selectively blocks hERG potassium channel.

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