Effects of a novel [formula omitted] (NMDA) receptor antagonist, 3,3′-dimethyl-3,4,3′,4′-tetrahydro-6,8,6′8′-tetramethoxy-[10,10′-bi-2-oxanthracene]-4,9,9′(1 H,1′ H)-triol 4-acetate (ES-242-1), on NMDA-induced increases of intracellular Ca 2+ concentration in cultured hippocampal neurons

Abstract

The effects of a novel N- methyl- d-aspartate (NMDA) receptor antagonists, ES-242-1 3,3′-dimethyl-3,4,3′,4′-tetrahydro-6,8,6′8′-tetramethoxy-[10,10′-bi-2-oxanthracene]-4,9,9′(1 H,1′ H)-triol 4-acetate, on NMDA-induced increases of intracellular Ca 2+ concentration in cultured hippocampal neurons were examined.ES-242-1 selectively blocked the NMDA-induced increase in intracellular free Ca 2+ concentration ([Ca 2+] i), but not the [Ca 2+] i increase stimulated by quisqualate or kainate. The effect of ES-242-1 appeared in the slow development of a blockade of [Ca 2+] i (half blocking time: 90sec) when 100 μM NMDA was applied with 10 μM ES-242-1, whereas the initial [Ca 2+] i rise was attenuated by 10 μM ES-242-1 when the latter was applied with a lower concentration of NMDA (10 μM). This is consistent with a previous observation that ES-242-1 binds to both the transmitter recognition site and the channel domain. The blockade by ES-242-1 was reversed by washing. In constrast, the blockade by MK-801 was not relieved easily by washing. These results suggest that ES-242-1 blocks the NMDA-induced [Ca 2+] i increase due to a combination of two well-recognized mechanisms, which are different from that of MK-801, at the NMDA receptor.