In Vitro electrophysiological activity of nerispirdine, a novel 4-aminopyridine derivative.
Summary 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(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 micromol/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 micromol/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.
Department of CNS Research, Sanofi-Aventis Inc., Bridgewater, New Jersey 08807, USA.
Craig
C
Smith
Sathapana
S
Kongsamut
Hongge
H
Wang
Junzhi
J
Ji
Jiesheng
J
Kang
David
D
Rampe
D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051662:Kv1.1 Potassium Channel / Q000037:antagonists & inhibitors*; D051663:Kv1.2 Potassium Channel / Q000037:antagonists & inhibitors*; D008564:Membrane Potentials / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051637:Shaker Superfamily of Potassium Channels; D026941:Sodium Channel Blockers / Q000494:pharmacology
D029721:Drosophila Proteins; D007211:Indoles; D051663:Kv1.2 Potassium Channel; D011725:Pyridines; C496929:Sh protein, Drosophila; D051637:Shaker Superfamily of Potassium Channels; D026941:Sodium Channel Blockers; D051662:Kv1.1 Potassium Channel; D015761:4-Aminopyridine; C101289:nerispirdine