Disease relevance of N-phenylmethanesulfonamide

• HERG/IKr channels are a prime target for the pharmacological management of arrhythmias and are selectively blocked by class III antiarrhythmic methanesulfonanilide drugs, such as dofetilide, E4031, and MK-499, at submicromolar concentrations [1].

High impact information on N-phenylmethanesulfonamide

• Here we use alanine-scanning mutagenesis to determine the structural basis for high-affinity drug block of HERG channels by MK-499, a methanesulfonanilide antiarrhythmic drug [2].
• BACKGROUND: Methanesulfonanilide derivatives, selective inhibitors of the rapidly activating component (I(Kr)) of the delayed rectifier potassium current (I(K)), prolong action potential duration (APD) of cardiac muscles with reverse frequency dependence, which limits their clinical use because of proarrhythmia [3].
• The major outward current in AT-1 cells is a delayed rectifier that displays prominent inward rectification, activates rapidly (eg, 182 +/- 27 milliseconds [mean +/- SEM] at + 20 mV, n = 12), exhibits biexponential deactivation kinetics, and is extremely sensitive to the methanesulfonanilide dofetilide (IC50, 12 nmol/L) [4].
• Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide [5].
• Although the residue (isoleucine at 647) is not in the recently reported methanesulfonanilide binding site, a single concentration of E-4031 (10 microM) was less effective to I647 mutant channels than wild type HERG channel [6].

Chemical compound and disease context of N-phenylmethanesulfonamide

• CONCLUSIONS: The regional differences in IK, in particular differences in its two components may underlie the regional disparity in APD, and that methanesulfonanilide class III antiarrhythmic agents such as E-4031 may cause a greater spatial inhomogeneity of ventricular repolarization, leading to re-entrant arrhythmias [7].

Biological context of N-phenylmethanesulfonamide

• In isolated, voltage-clamped SAN cells, outward currents evoked by depolarizing steps (greater than -40 mV) were strongly inhibited by the class III methanesulfonanilide compound E-4031 (1-2.5 microM), and the deactivation "tail" currents that occurred during repolarization to a membrane potential of -45 mV were completely blocked [8].

Anatomical context of N-phenylmethanesulfonamide

• The biophysical properties of currents recorded from HERG expressing Xenopus oocytes are similar to those of a cardiac K+ current, I(Kr), but the characteristic nanomolar methanesulfonanilide sensitivity has not been demonstrated [9].

Gene context of N-phenylmethanesulfonamide

• The hERG also expresses an inwardly rectifying, methanesulfonanilide-sensitive K+ current [10].
• While displacement of [3H]dofetilide, a potent methanesulfonanilide hERG blocker, from cells heterologously expressing hERG has been suggested as a screening assay, questions have been raised about its predictive value [11].

Analytical, diagnostic and therapeutic context of N-phenylmethanesulfonamide

• Determination of an anti-inflammatory methanesulfonanilide in plasma by high-speed liquid chromatography [12].

References