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ACS Chem Neurosci
2013 Feb 20;42:255-60. doi: 10.1021/cn300180a.
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Key binding interactions for memantine in the NMDA receptor.
Limapichat W
,
Yu WY
,
Branigan E
,
Lester HA
,
Dougherty DA
.
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Memantine (Namenda) is prescribed as a treatment for moderate to severe Alzheimer's Disease. Memantine functions by blocking the NMDA receptor, but the key binding interactions between drug and receptor are not fully elucidated. To determine key binding interactions of memantine, we made side-by-side comparisons of IC(50) for memantine and amantadine, a structurally related drug, in the GluN1/GluN2B NMDA receptor. We identified hydrophobic binding pockets for the two methyl groups on memantine formed by the residues A645 and A644 on the third transmembrane helices of GluN1 and GluN2B, respectively. Moreover, we found that while adding two methyl groups to amantadine to produce memantine greatly improves affinity, adding a third methyl group to produce the symmetrical trimethylamantadine diminished affinity. Our results provide a better understanding of chemical-scale interactions between memantine and the NMDA channel, which will potentially benefit the development of new drugs for neurodegenerative diseases involving NMDA receptors.
Antonov,
Voltage-dependent interaction of open-channel blocking molecules with gating of NMDA receptors in rat cortical neurons.
1996, Pubmed
Antonov,
Voltage-dependent interaction of open-channel blocking molecules with gating of NMDA receptors in rat cortical neurons.
1996,
Pubmed
Blanke,
The NR1 M3 domain mediates allosteric coupling in the N-methyl-D-aspartate receptor.
2008,
Pubmed
,
Xenbase
Blanpied,
Trapping channel block of NMDA-activated responses by amantadine and memantine.
1997,
Pubmed
Blanpied,
Amantadine inhibits NMDA receptors by accelerating channel closure during channel block.
2005,
Pubmed
Bormann,
Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels.
1989,
Pubmed
Chang,
The activation gate and gating mechanism of the NMDA receptor.
2008,
Pubmed
,
Xenbase
Chang,
Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
2008,
Pubmed
,
Xenbase
Chen,
Pharmacological implications of two distinct mechanisms of interaction of memantine with N-methyl-D-aspartate-gated channels.
2005,
Pubmed
,
Xenbase
Chen,
The chemical biology of clinically tolerated NMDA receptor antagonists.
2006,
Pubmed
Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed
Johnson,
Mechanism of action of memantine.
2006,
Pubmed
Kashiwagi,
Channel blockers acting at N-methyl-D-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore.
2002,
Pubmed
,
Xenbase
Kotermanski,
Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine.
2009,
Pubmed
Kuner,
A common architecture for K+ channels and ionotropic glutamate receptors?
2003,
Pubmed
Lemoine,
Ligand-gated ion channels: new insights into neurological disorders and ligand recognition.
2012,
Pubmed
Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed
Madden,
The structure and function of glutamate receptor ion channels.
2002,
Pubmed
Otton,
Quantification of the Mg2+-induced potency shift of amantadine and memantine voltage-dependent block in human recombinant GluN1/GluN2A NMDARs.
2011,
Pubmed
,
Xenbase
Parsons,
Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system--too little activation is bad, too much is even worse.
2007,
Pubmed
Parsons,
Memantine does not show intracellular block of the NMDA receptor channel.
2008,
Pubmed
,
Xenbase
Sobolevsky,
Subunit-specific contribution of pore-forming domains to NMDA receptor channel structure and gating.
2007,
Pubmed
,
Xenbase
Sobolevsky,
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.
2009,
Pubmed
Sobolevsky,
Staggering of subunits in NMDAR channels.
2002,
Pubmed
,
Xenbase
Sobolevsky,
Interaction of memantine and amantadine with agonist-unbound NMDA-receptor channels in acutely isolated rat hippocampal neurons.
1998,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Wada,
NR3A modulates the outer vestibule of the "NMDA" receptor channel.
2006,
Pubmed
,
Xenbase
Wilkinson,
A review of the effects of memantine on clinical progression in Alzheimer's disease.
2012,
Pubmed
Witt,
Memantine hydrochloride.
2004,
Pubmed
Wollmuth,
Structure and gating of the glutamate receptor ion channel.
2004,
Pubmed
Yuan,
Conserved structural and functional control of N-methyl-D-aspartate receptor gating by transmembrane domain M3.
2005,
Pubmed
