Discovery of N-(3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl)-4-methoxybenzenesulfamide (sulcardine) as a novel anti-arrhythmic agent
Abstract
Aim: To investigate the anti-arrhythmic effects of sulfamide analogues of changrolin and to characterize the sulfate of compound 6f (sulcardine sulfate, Sul) as a novel anti-arrhythmic agent.
Methods: The anti-arrhythmic effects of compounds were studied against aconitine-induced arrhythmias in rats and ouabain-induced arrhythmias in guinea pigs. The effects of Sul on transmembrane action potentials were investigated in isolated rabbit sinoatrial nodes and guinea-pig papillary muscles using intracellular recording. With a whole-cell recording technique, the effects of Sul on sodium current, calcium current, and potassium currents were examined in isolated single guinea-pig ventricular myocytes.
Results: In aconitine-induced arrhythmias of rats, sulfamide analogues of changrolin (4, 5, and 6a–6p) exhibited various anti-arrhythmic activities. The sulfate of compound 6f (Sul) increased the amount of aconitine required to induce arrhythmias in each treated animal. The ED50 value of Sul in rats was 196 mg/kg. In ouabain-induced arrhythmias of guinea pigs, 25, 50, and 100 mg/kg doses of Sul increased the dose of ouabain required to induce VP, VT, and VF in a dose-dependent manner. In papillary preparations, Sul produced a concentration-dependent decrease in APA and Vmax, prolonged APD90 and ERP, whereas RP was unaffected. In the spontaneously beating sinus nodes, Sul reduced APA and Vmax in a concentration-dependent manner. The whole-cell recording studies revealed that Sul produced a reversible reduction in INa (IC50=26.9 μmol/L) and ICa,L(IC50=69.2 μmol/L), whereas the inward rectifier (IK1) and the delayed rectifier potassium currents (IK) were unaffected.
Conclusion: As a multi-ion channel blocker, Sul may have potent efficacy in anti-atrial and ventricular arrhythmias.
Keywords:
Methods: The anti-arrhythmic effects of compounds were studied against aconitine-induced arrhythmias in rats and ouabain-induced arrhythmias in guinea pigs. The effects of Sul on transmembrane action potentials were investigated in isolated rabbit sinoatrial nodes and guinea-pig papillary muscles using intracellular recording. With a whole-cell recording technique, the effects of Sul on sodium current, calcium current, and potassium currents were examined in isolated single guinea-pig ventricular myocytes.
Results: In aconitine-induced arrhythmias of rats, sulfamide analogues of changrolin (4, 5, and 6a–6p) exhibited various anti-arrhythmic activities. The sulfate of compound 6f (Sul) increased the amount of aconitine required to induce arrhythmias in each treated animal. The ED50 value of Sul in rats was 196 mg/kg. In ouabain-induced arrhythmias of guinea pigs, 25, 50, and 100 mg/kg doses of Sul increased the dose of ouabain required to induce VP, VT, and VF in a dose-dependent manner. In papillary preparations, Sul produced a concentration-dependent decrease in APA and Vmax, prolonged APD90 and ERP, whereas RP was unaffected. In the spontaneously beating sinus nodes, Sul reduced APA and Vmax in a concentration-dependent manner. The whole-cell recording studies revealed that Sul produced a reversible reduction in INa (IC50=26.9 μmol/L) and ICa,L(IC50=69.2 μmol/L), whereas the inward rectifier (IK1) and the delayed rectifier potassium currents (IK) were unaffected.
Conclusion: As a multi-ion channel blocker, Sul may have potent efficacy in anti-atrial and ventricular arrhythmias.