SYNTHESIS AND SAR OF 2H-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDE-3-CARBOXYLIC ACID-DERIVATIVES AS NOVEL POTENT GLYCINE ANTAGONISTS OF THE NMDA RECEPTOR-CHANNEL COMPLEX

A new series of 2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic ac ids was synthesized. Most compounds demonstrated excellent binding aff inities at the glycine binding site of the NMDA receptor-channel compl ex. A member of this series, RPR 104632 displaces strychnine-insensiti ve [3H]-DCKA binding with high potency (IC50 = 8 nM) and stereoselecti vity: the levorotatory isomer (-)-8k (IC50 = 4 nM) is about 500-times more potent than the dextrorotatory isomer (+)-8k (IC50 = 1880 nM). In in vitro and in vivo models, RPR 104632 is a potent antagonist of cen tral NMDA receptor activation.