Benzyloxybenzylammonium chlorides: Simple amine salts that display anticonvulsant activity |
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Authors: | Hyosung Lee Alexander S. Gold Xiao-Fang Yang Rajesh Khanna Harold Kohn |
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Affiliation: | 1. Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA;2. Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;3. Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;4. Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA;5. Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290, USA |
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Abstract: | Several antiepileptic drugs exert their activities by inhibiting Na+ currents. Recent studies demonstrated that compounds containing a biaryl-linked motif (Ar-X-Ar′) modulate Na+ currents. We, and others, have reported that compounds with an embedded benzyloxyphenyl unit (ArOCH2Ar′, OCH2 = X) exhibit potent anticonvulsant activities. Here, we show that benzyloxybenzylammonium chlorides (+H3NCH2C6H4OCH2Ar′ Cl?) displayed notable activities in animal seizure models. Electrophysiological studies of 4-(2′-trifluoromethoxybenzyloxy)benzylammonium chloride (9) using embryonic cortical neurons demonstrated that 9 promoted both fast and slow inactivation of Na+ channels. These findings suggest that the potent anticonvulsant activities of the earlier compounds were due, in part, to the benzyloxyphenyl motif and provide support for the use of the biaryl-linked pharmacophore in future drug design efforts. |
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Keywords: | Antiepileptic agents Biaryl-linked motif Benzyloxybenzylammonium chlorides |
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