EFFECTS OF A NOVEL N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ANTAGONIST, Y-[10,10'-BI-2-OXANTHRACENE]-4,9,9'-(1H,1'H)-TRIOL 4-ACETATE (ES-242-1), ON NMDA-INDUCED INCREASES OF INTRACELLULAR CA2+ CONCENTRATION IN CULTURED HIPPOCAMPAL

The effects of a novel N-methyl-D-aspartate (NMDA) receptor antagonist , ES-242-1 y-[10,10'-bi-2-oxanthracene]-4,9,9'-(1H,1'H)-triol 4-acetat e), on NMDA-induced increases of intracellular Ca2+ concentration in c ultured hippocampal neurons were examined. ES-242-1 selectively blocke d the NMDA-induced increase in intracellular free Ca2+ concentration ( [Ca2+](i)), but not the [Ca2+](i) increase stimulated by quisqualate o r kainate. The effect of ES-242-1 appeared in the slow development of a blockade of [Ca2+](i) (half blocking time: 90 sec) when 100 mu M NMD A was applied with 10 mu M ES-242-1, whereas the initial [Ca2+](i) ris e was attenuated by 10 mu M ES-242-1 when the latter was applied with a lower concentration of NMDA (10 mu M). This is consistent with a pre vious observation that ES-242-1 binds to both the transmitter recognit ion site and the channel domain. The blockade by ES-242-1 was reversed by washing. In contrast, the blockade by MK-801 was not relieved easi ly by washing. These results suggest that ES-242-1 blocks the NMDA-ind uced [Ca2+](i) increase due to a combination of two well-recognized me chanisms, which are different from that of MK-801, at the NMDA recepto r.