title: Substituted 2-benzothiazolamines as sodium flux inhibitors: quantitative structure-activity relationships and anticonvulsant activity.
abstract: Thirty-two aryl-substituted 2-benzothiazolamines have been tested for their ability to modulate sodium flux in rat cortical slices. A QSAR analysis, applied to these derivatives, showed a trend toward increasing potency as sodium flux inhibitors with increasing lipophilicity, decreasing size, and increasing electron withdrawal of the benzo ring substituents. Additionally, 4- or 5-substitution of the benzo ring was found to decrease potency. The combination of increased lipophilicity, small size, and electron withdrawal severely limited which groups were tolerated on the benzo ring, thus suggesting that the optimal substitution patterns have been prepared within this series. Nine of these compounds were potent inhibitors of veratridine-induced sodium flux (NaFl). These nine compounds also proved to be anticonvulsant in the maximal electroshock (MES) assay. Fourteen additional 2-benzothiazolamines demonstrated activity in the MES screen, yet exhibited no activity in the NaFl assay. These derivatives may be interacting at the sodium channel in a manner not discernible by the flux paradigm, or they may be acting by an alternative mechanism in vivo.
authors.affiliation: Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
authors.forename: S J
authors.initials: SJ
authors.lastname: Hays
authors.forename: M J
authors.initials: MJ
authors.lastname: Rice
authors.forename: D F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: G
authors.initials: G
authors.lastname: Johnson
authors.forename: R D
authors.initials: RD
authors.lastname: Schwarz
authors.forename: D K
authors.initials: DK
authors.lastname: Boyd
authors.forename: L F
authors.initials: LF
authors.lastname: Copeland
authors.forename: M G
authors.initials: MG
authors.lastname: Vartanian
authors.forename: P A
authors.initials: PA
authors.lastname: Boxer
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001259:Ataxia / Q000188:drug therapy; D052160:Benzothiazoles; D004597:Electroshock; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D052160:Benzothiazoles; D015222:Sodium Channels; D013844:Thiazoles; D012964:Sodium; C005465:benzothiazole