In Vitro electrophysiological activity of nerispirdine, a novel 4-aminopyridine derivative

P>The non-selective K+ channel blocker 4-aminopyridine (4-AP) has shown clinical efficacy in the treatment of neurological disorders such as multiple sclerosis. The clinical usefulness of 4-AP is hampered by its ability to produce seizures. Nerispirdine, an analogue of 4-AP, is currently under clinical investigation for the treatment of multiple sclerosis. In contrast with 4-AP, nerispirdine is not proconvulsant, suggesting mechanistic differences between the two drugs. Using whole-cell patch-clamp electrophysiology, we compared the effects of 4-AP and nerispirdine on the cloned human K+ channels K(v)1.1 and K(v)1.2, expressed in Chinese hamster ovary cells, and on voltage-dependent Na+ channels recorded from human SH-SY5Y cells. Nerispirdine inhibited K(v)1.1 and K(v)1.2 with IC50 values of 3.6 and 3.7 mu mol/L, respectively. 4-Aminopyridine was approximately 50-fold less potent at blocking these channels. Nerispirdine also inhibited voltage-dependent Na+ channel currents recorded from human SH-SY5Y cells with an IC50 of 11.9 mu mol/L when measured from a -70 mV holding potential. In contrast, 4-AP had no effect on Na+ channel currents. The results demonstrate that nerispirdine, like 4-AP, can inhibit axonal K+ channels and that this mechanism may underlie the ability of the drug to enhance neuronal conduction. Unlike 4-AP, nerispirdine can also inhibit neuronal Na+ channels, a mechanism that may explain why nerispirdine lacks proconvulsant activity.