Abstract
This study characterizes the trapping of block ofN-methyl-d-aspartic acid (NMDA)-induced currents by three structurally distinct, use-dependent NMDA receptor antagonists with similar rapid on-off rates. The antagonism of whole-cell currents in cultured rat cortical neurons by AR-R15896AR, ketamine, and memantine was examined. All three compounds produced a steady-state block after a 30-s coapplication, which was fully relieved after 50 s of NMDA exposure. The amplitudes of block caused by 50 μM AR-R15896AR, 10 μM ketamine, or 10 μM memantine were not significantly different, being 82 ± 1%, 80 ± 2%, and 81 ± 2%, respectively. All three NMDA receptor antagonists exhibited trapping of block that was not significantly increased by extending the agonist/antagonist coapplication beyond 30 s. Although the initial blocks were similar, after 120 s of washout without agonist present, there were significant differences in trapping of block between antagonists, as only 54 ± 3% of the AR-R15896AR block, 86 ± 1% of the ketamine block, and 71 ± 4% of the memantine block remained trapped. The lack of complete trapping is consistent with closed-channel egress by these compounds. Higher antagonist concentrations produced larger initial blocks, but the degree of trapping block was not significantly different from that at lower antagonist concentrations. The results demonstrate that differences in the degree of trapping exist among use-dependent NMDA receptor antagonists even when on and off rates are similar. These differences are correlated with measures of therapeutic index.
Footnotes
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Send reprint requests to: Geoff Mealing, Institute for Biological Sciences, National Research Council of Canada, Building M54, Montreal Rd., Ottawa, Ontario, Canada, K1A 0R6. E-mail:geoff.mealing{at}nrc.ca
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↵1 Funding for this work was provided in part by the Astra Canadian Neuroprotection Network.
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↵2 Present address: Astra Arcus USA, Rochester, NY 14602.
- Abbreviations:
- NMDA
- N-methyl-d-aspartic acid
- ADCI
- 5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine
- AP-5
- 2-amino-5-phosphonopentanoic acid
- AR-R15896AR (formerly called ARL 15896AR or FPL 15896AR)
- (S)-α-phenyl-2-pyridineethanamine dihydrochloride
- 9-AA
- 9-aminoacridine
- EGTA
- ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- MEM
- Eagle’s minimal essential medium
- MK-801
- dizocilpine
- PBS
- Dulbecco’s phosphate-buffered saline
- Received April 21, 1998.
- Accepted July 31, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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