N-Methyl-D-aspartate (NMDA) antagonists reduce ischemic brain damage and associated hypermotility. Two potent, selective and competitive NMDA antagonists, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) and 4-(3-phosphonopropyl)-2-piperazine-carboxylic acid (CPP), were characterized in the gerbil ischemia model with respect to dose-response and time course effects. Both drugs were effective in reducing ischemia-induced hippocampal brain damage as well as hypermotility. In this model, CGS 19755 was more potent than CPP, and had protective effects when given after longer delays between ischemia and drug administration.