Nelson M E, Albuquerque E X
Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore 21201.
Mol Pharmacol. 1994 Jul;46(1):151-60.
The effects of alkylene bis-9,9'-aminoacridines and 1,2,3,4-tetrahydro-9-aminoacridine (THA) were studied on single-channel currents activated by N-methyl-D-aspartate (NMDA) in outside-out patches from cultured rat hippocampal neurons. These compounds reduced the channel open times with concentration and voltage dependence, which was consistent with an open-channel blockade mechanism of action. In nominally Mg(2+)-free solutions, the forward blocking rate constants for 1,2-propane-bis-9,9'-aminoacridine, 1,4-butane-9,9'-aminoacridine, and THA were 1.1 x 10(8), 1.4 x 10(8), and 3.5 x 10(7) M-1 sec-1, respectively, at a holding potential of -80 mV. The unblocking rate constants for the bis-9-aminoacridines were similar and in the range of 7 sec-1, whereas THA had an unblocking rate constant of approximately 6.2 x 10(3) sec-1. In the presence of Mg2+ (approximately 5 microM), the predictions of the model for open-channel blockade by the 9-aminoacridines were invalid, because the relationships between the channel lifetimes and 9-aminoacridine concentrations were not linear. The effects of Mg2+ (approximately 0-50 microM) on the open-channel blockade of the NMDA receptor by the 9-aminoacridines were evaluated further by measuring the burst times in the presence of 1,2-propane-bis-9,9'-aminoacridine (5 microM). The results suggested that the interactions of 9-aminoacridines and Mg2+ with the ion channel of the NMDA receptor were not mutually exclusive. Simultaneous occupancy of the NMDA receptor ion channel by Mg2+ and a channel-blocking organic cation could be a common mechanism of channel blockade for this receptor under physiological conditions.
研究了亚烷基双-9,9'-氨基吖啶和1,2,3,4-四氢-9-氨基吖啶（THA）对培养的大鼠海马神经元外向膜片中N-甲基-D-天冬氨酸（NMDA）激活的单通道电流的影响。这些化合物以浓度和电压依赖性方式缩短通道开放时间，这与开放通道阻断作用机制一致。在名义上无Mg(2+) 的溶液中，在-80 mV的钳制电位下，1,2-丙烷双-9,9'-氨基吖啶、1,4-丁烷-9,9'-氨基吖啶和THA的正向阻断速率常数分别为1.1×10(8)、1.4×10(8) 和3.5×10(7) M-1秒-1。双-9-氨基吖啶的解除阻断速率常数相似，在7秒-1范围内，而THA的解除阻断速率常数约为6.2×10(3) 秒-1。在存在Mg2+（约5 microM）的情况下，9-氨基吖啶对开放通道阻断的模型预测无效，因为通道寿命与9-氨基吖啶浓度之间的关系不是线性的。通过测量在1,2-丙烷双-9,9'-氨基吖啶（5 microM）存在下的爆发时间，进一步评估了Mg2+（约0 - 50 microM）对9-氨基吖啶对NMDA受体开放通道阻断的影响。结果表明，9-氨基吖啶和Mg2+ 与NMDA受体离子通道的相互作用不是相互排斥的。在生理条件下，Mg2+ 和通道阻断有机阳离子同时占据NMDA受体离子通道可能是该受体通道阻断的常见机制。
