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

Abstract

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.

• Authors: Craig Smith, Sathapana Kongsamut, Hongge Wang, Junzhi Ji, Jiesheng Kang, David Rampe
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 36 Issue 11 Pg. 1104-9 (Nov 2009) ISSN: 1440-1681 [Electronic] Australia
• PMID: 19413590 (Publication Type: Journal Article)

Chemical References

• Drosophila Proteins
• Indoles
• Kv1.2 Potassium Channel
• Pyridines
• Sh protein, Drosophila
• Shaker Superfamily of Potassium Channels
• Sodium Channel Blockers
• Kv1.1 Potassium Channel
• 4-Aminopyridine
• nerispirdine

Topics

• 4-Aminopyridine (analogs & derivatives, pharmacology)
• Animals
• CHO Cells
• Cricetinae
• Cricetulus
• Drosophila Proteins
• Female
• Humans
• Indoles (pharmacology)
• Kv1.1 Potassium Channel (antagonists & inhibitors)
• Kv1.2 Potassium Channel (antagonists & inhibitors)
• Membrane Potentials (drug effects)
• Pyridines (pharmacology)
• Shaker Superfamily of Potassium Channels
• Sodium Channel Blockers (pharmacology)