BLOCK OF THE N-METHYL-D-ASPARTATE RECEPTOR BY REMACEMIDE AND ITS DES-GLYCINE METABOLITE

The anticonvulsant and neuroprotective properties of remacemide )-2-am ino-N-(1-methyl-1,2-diphenylethyl)acetamide] and its active des-glycin e metabolite [(+/-)-1-methyl-1,2-diphenylethylamine] may result in par t from blockade of N-methyl-D-aspartate (NMDA) receptors, The blocking actions of the remacemide enantiomers and their des-glycinates were i nvestigated in whole cell voltage-clamp recordings from cultured rat h ippocampal neurons and in binding studies with [H-3]dizocilpine in rat forebrain membranes. (+/-)-Remacemide caused a rapid and reversible i nhibition of NMDA-evoked current; the R(+)- and S(-)-enantiomers were roughly equipotent (IC50 values at -60 mV, 67 and 75 mu M, respectivel y). In contrast, the block by the S(+)- and R(-)-des-glycine analogs w as slower, more potent and occurred in a stereoselective fashion (IC50 values, 0.7 and 4 mu M). The block by S(+)-des-glycine remacemide was strongly use- and voltage-dependent, and, in addition, could be occlu ded by Mg++, indicating that it occurs by an open channel mechanism, I n contrast, the block by R(+)-remacemide was only partially voltage-de pendent, suggesting that it occurs by both channel blocking and noncha nnel blocking (allosteric) mechanisms. Support for an allosteric mecha nism was obtained in nonequilibrium [H-3]dizocilpine binding studies w here it was observed that 100 mu M R(+)-remacemide slowed the dissocia tion of the radioligand [whereas 10 mu M S(+)-des-glycine remacemide d id not]. Neither R(+)-remacemide nor S(+)-desglycine remacemide inhibi ted currents evoked by kainate, ha-amino-3-hydroxy-5-methyl-4-isoxazol eproprionate or gamma-aminobutyric acid. We conclude that des-glycine remacemide is a potent and selective channel blocking NMDA receptor an tagonist, whereas remacemide is weaker and inhibits NMDA receptors by both channel blocking and nonchannel blocking actions.