Benzyloxybenzylammonium chlorides: Simple amine salts that display anticonvulsant activity

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.