Effects of a novel N-methyl-D-aspartate (NMDA) receptor antagonist, 3,3'-dimethyl-3,4,3',4'-tetrahydro-6,8,6',8'-tetramethoxy-[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 neurons.
The effects of a novel N-methyl-D-aspartate (NMDA) receptor antagonist, ES-242-1 (3,3'-dimethyl-3,4,3',4'-tetrahydro-6,8,6',8'-tetramethoxy-[10,10' - bi-2-oxanthracene]-4,9,9'-(1H,1'H)-triol 4-acetate), on NMDA-induced increases of intracellular Ca2+ concentration in cultured hippocampal neurons were examined. ES-242-1 selectively blocked the NMDA-induced increase in intracellular free Ca2+ concentration ([Ca2+]i), but not the [Ca2+]i increase stimulated by quisqualate or 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 microM NMDA was applied with 10 microM ES-242-1, whereas the initial [Ca2+]i rise was attenuated by 10 microM ES-242-1 when the latter was applied with a lower concentration of NMDA (10 microM). 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 contrast, the blockade by MK-801 was not relieved easily by washing. These results suggest that ES-242-1 blocks the NMDA-induced [Ca2+]i increase due to a combination of two well-recognized mechanisms, which are different from that of MK-801, at the NMDA receptor.
Tsukuda
E
E
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co. Ltd., Japan.
Toki
S
S
Nozawa
M
M
Matsuda
Y
Y
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D011714:Pyrans / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013696:Temperature
D011714:Pyrans; D016194:Receptors, N-Methyl-D-Aspartate; C073561:ES 242-1; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D002118:Calcium