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.
Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA.
Hyosung
H
Lee
Alexander S
AS
Gold
Xiao-Fang
XF
Yang
Rajesh
R
Khanna
Harold
H
Kohn
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D050339:Benzylammonium Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects*; D010647:Phenyl Ethers / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D050339:Benzylammonium Compounds; D010647:Phenyl Ethers
Antiepileptic agents; Benzyloxybenzylammonium chlorides; Biaryl-linked motif; Na(+) current inhibition