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In Vitro electrophysiological activity of nerispirdine, a novel 4‐aminopyridine derivative
Author(s) -
Smith Craig,
Kongsamut Sathapana,
Wang Hongge,
Ji Junzhi,
Kang Jiesheng,
Rampe David
Publication year - 2009
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2009.05200.x
Subject(s) - 4 aminopyridine , electrophysiology , chinese hamster ovary cell , patch clamp , pharmacology , chemistry , sodium channel , in vitro , biophysics , neuroscience , potassium channel , medicine , biochemistry , biology , receptor , sodium , organic chemistry
Summary1 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 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. 3 Nerispirdine inhibited K v 1.1 and K v 1.2 with IC 50 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 IC 50 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.