9-Aminoacridines act at a site different from that for Mg2+ in blockade of the N-methyl-D-aspartate receptor channel.
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.
Nelson
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Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore 21201.
Albuquerque
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D000585:Aminacrine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects*; D008274:Magnesium / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*
D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D000585:Aminacrine; D008274:Magnesium