Benzyloxybenzylammonium chlorides: Simple amine salts that display anticonvulsant activity

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 (ArOCH 2 Ar′, OCH 2  = X) exhibit potent anticonvulsant activities. Here, we show that benzyloxybenzylammonium chlorides ( + H 3 NCH 2 C 6 H 4 OCH 2 Ar′ 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.