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

• 1 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.
• 2 Using whole‐cell patch‐clamp electrophysiology, we compared the effects of 4‐AP and nerispirdine on the cloned human K⁺ channels K_v1.1 and K_v1.2, expressed in Chinese hamster ovary cells, and on voltage‐dependent Na⁺ channels recorded from human SH‐SY5Y cells.
• 3 Nerispirdine inhibited K_v1.1 and K_v1.2 with IC₅₀ values of 3.6 and 3.7 μmol/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 μmol/L when measured from a –70 mV holding potential. In contrast, 4‐AP had no effect on Na⁺ channel currents.
• 4 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.