(Biphenyl-4-yl)methylammonium Chlorides: Potent Anticonvulsants That Modulate Na+ Currents

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• 作者：Hyosung Lee ; Ki Duk Park ; Xiao-Fang Yang ; Erik T. Dustrude ; Sarah M. Wilson ; Rajesh Khanna ; Harold Kohn
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5931-5939
• 全文大小：513K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

We have reported that compounds containing a biaryl linked unit (Ar-X-Ar鈥? modulated Na⁺ currents by promoting slow inactivation and fast inactivation processes and by inducing frequency (use)-dependent inhibition of Na⁺ currents. These electrophysiological properties have been associated with the mode of action of several antiepileptic drugs. In this study, we demonstrate that the readily accessible (biphenyl-4-yl)methylammonium chlorides (compound class B) exhibited a broad range of anticonvulsant activities in animal models, and in the maximal electroshock seizure test the activity of (3鈥?trifluoromethoxybiphenyl-4-yl)methylammonium chloride (8) exceeded that of phenobarbital and phenytoin upon oral administration to rats. Electrophysiological studies of 8 using mouse catecholamine A-differentiated cells and rat embryonic cortical neurons confirmed that 8 promoted slow and fast inactivation in both cell types but did not affect the frequency (use)-dependent block of Na⁺ currents.