Abstract
Unlike other N-methyl-d-aspartate receptor (NMDAR) antagonists, clinical trials have shown that memantine is clinically tolerated and effective in the treatment of Alzheimer's disease. The mechanism for memantine tolerability, however, remains contentious but may be partly explained by its uncompetitive antagonism. The specific site of memantine block in the NMDAR channel interacts with magnesium and is assumed to be at or near a narrow constriction representing the channel selectivity filter. A second, very low-affinity site of memantine action has also been reported. Here, using mutational analysis and substituted cysteine accessibility methods on recombinant NR1/NR2A NMDARs expressed in Xenopus oocytes, we precisely localize both the specific and second memantine-blocking sites. Intriguingly, memantine interacts with its specific blocking site in the same fashion as intracellular rather than extracellular Mg2+. Thus, the N-site asparagine (N) in the M2 region of the NR1 subunit represents the dominant site for uncompetitive antagonism by memantine. The N and N + 1 site asparagines in NR2A produce strong electrostatic interactions with memantine. In contrast, the second (superficial) memantine-blocking site, located at the extracellular vestibule of the channel, appears to be nonspecific and overlaps the site occupied by the nonspecific pore blocker hexamethonium. Residues in the post-M3 segment of the NR1 subunit are not directly involved in memantine binding. The distinct patterns of interaction and the relative degree of affinity of memantine for these two binding sites contribute to the drug's excellent pharmacological profile of clinical tolerability. In the future, these parameters should be considered in searching for improved neuroprotective agents in this class.
Footnotes
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This work was supported in part by an American Heart Association Scientist Development Grant (to H.-S. V. Chen), National Institutes of Health Grants P01 HD29587, R01 EY09024, and R01 EY05477, and a Senior Scholar Award from the Ellison Medical Foundation (to S. A. Lipton).
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doi:10.1124/jpet.105.085142.
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ABBREVIATIONS: NMDAR, N-methyl-d-aspartate receptor; MK-801, dizocilpine; MTSEA, 2-aminoethyl-methanethiosulphonate; SCAM, substituted cysteine accessibility method; MEM, memantine; MTS, methanethiosulfonate; RDM, relative degree of modulation; HME, hexamethonium.
- Received February 25, 2005.
- Accepted May 11, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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