The anticonvulsant and neuroprotective properties of remacemide [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)acetamide] and its active des-glycine metabolite [(+/-)-1-methyl-1,2-diphenylethylamine] may result in part from blockade of N-methyl-D-aspartate (NMDA) receptors. The blocking actions of the remacemide enantiomers and their des-glycinates were investigated in whole cell voltage-clamp recordings from cultured rat hippocampal neurons and in binding studies with [3H]dizocilpine in rat forebrain membranes. (+/-)-Remacemide caused a rapid and reversible inhibition of NMDA-evoked current; the R(+)- and S(-)-enantiomers were roughly equipotent (IC50 values at -60 mV, 67 and 75 microM, respectively). In contrast, the block by the S(+)- and R(-)-des-glycine analogs was slower, more potent and occurred in a stereoselective fashion (IC50 values, 0.7 and 4 microM). The block by S(+)-des-glycine remacemide was strongly use- and voltage-dependent, and, in addition, could be occluded by Mg++, indicating that it occurs by an open channel mechanism. In contrast, the block by R(+)-remacemide was only partially voltage-dependent, suggesting that it occurs by both channel blocking and nonchannel blocking (allosteric) mechanisms. Support for an allosteric mechanism was obtained in nonequilibrium [3H]dizocilpine binding studies where it was observed that 100 microM R(+)-remacemide slowed the dissociation of the radioligand [whereas 10 microM S(+)-des-glycine remacemide did not]. Neither R(+)-remacemide nor S(+)-des-glycine remacemide inhibited currents evoked by kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate or gamma-aminobutyric acid. We conclude that des-glycine remacemide is a potent and selective channel blocking NMDA receptor antagonist, whereas remacemide is weaker and inhibits NMDA receptors by both channel blocking and nonchannel blocking actions.