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The effects of 4-chloro-3-nitro-N-butylbenzenesulfonamide (SMD2) on K V 3.1 channels, heterologous expressed in L-929 cells, were studied with the whole cell patch-clamp technique. SMD2 blocks K V 3.1 in a reversible and use-dependent manner, with IC 50 around 10 µM, and a Hill coefficient around 2. Although the conductance vs. voltage relationship in control condition can be described by a single Boltzmann function, two terms are necessary to describe the data in the presence of SMD2. The activation and deactivation time constants are weakly voltage dependent both for control and in the presence of SMD2. SMD2 does not change the channel selectivity and tail currents show a typical crossover phenomenon. The time course of inactivation has a fast and a slow component, and SMD2 significantly decreased their values. Steady-state inactivation is best described by a Boltzmann equation with V 1/2 (the voltage where the probability to find the channels in the inactivated state is 50%) and K (slope factor) equals to -22.9 ± 1.5 mV and 5.3 ± 0.9 mV for control, and -30.3 ± 1.3 mV and 6 ± 0.8 mV for SMD2, respectively. The action of SMD2 is enhanced by high frequency stimulation, and by the time the channel stays open. Taken together, our results suggest that SMD2 blocks the open conformation of K V 3.1. From a pharmacological and therapeutic point of view, N-alkylsulfonamides may constitute a new class of pharmacological modulators of K V 3.1.