SUBSTITUTED 2-BENZOTHIAZOLAMINE AS SODIUM FLUX INHIBITORS - QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS AND ANTICONVULSANT ACTIVITY

Thirty-two aryl-substituted 2-benzothiazolamines have been tested for their ability to modulate sodium flux in rat cortical slices. A QSAR a nalysis, applied to these derivatives, showed a trend toward increasin g potency as sodium flux inhibitors with increasing lipophilicity, dec reasing size, and increasing electron withdrawal of the benzo ring sub stitutents. Additionally, 4- or 5-substitution of the benzo ring was f ound 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 substit ution patterns have been prepared within this series. Nine of these co mpounds were potent inhibitors of veratridine-induced sodium flux (NaF l). These nine compounds also proved to be anticonvulsant in the maxim al 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 cha nnel in a manner not discernible by the flux paradigm, or they may be acting by an alternative mechanism in vivo.