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Key Binding Interactions for Memantine in the NMDA Receptor

Limapichat, Walrati and Yu, Wesley Y. and Branigan, Emma and Lester, Henry A. and Dougherty, Dennis A. (2013) Key Binding Interactions for Memantine in the NMDA Receptor. ACS Chemical Neuroscience, 4 (2). pp. 255-260. ISSN 1948-7193. PMCID PMC3751542. doi:10.1021/cn300180a. https://resolver.caltech.edu/CaltechAUTHORS:20130328-101734866

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/cn300180aDOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751542/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2012 American Chemical Society. Received: October 12, 2012; Accepted: November 29, 2012; Published: November 29, 2012. This work was supported by the NIH (NS 34407 to D.A.D.). Author Contributions: Contributed to research design: W.L., E.B., W.Y., H.A.L., and D.A.D. conducted experiments: W.L., E.B., and W.Y. Performed data analysis: W.L., E.B., W.Y., H.A.L., and D.A.D. Writing of the manuscript: W.L., W.Y., H.A.L., and D.A.D. We thank Dr. Kathryn McMenimen for helpful discussions.
Funders:
Funding AgencyGrant Number
NIHNS 34407
Subject Keywords:Memantine; open-channel blocker; amantadine; unnatural amino acid mutagenesis
Issue or Number:2
PubMed Central ID:PMC3751542
DOI:10.1021/cn300180a
Record Number:CaltechAUTHORS:20130328-101734866
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130328-101734866
Official Citation:Key Binding Interactions for Memantine in the NMDA Receptor Walrati Limapichat, Wesley Y. Yu, Emma Branigan, Henry A. Lester, and Dennis A. Dougherty ACS Chemical Neuroscience20134 (2), 255-260
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:37670
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Apr 2013 23:28
Last Modified:09 Nov 2021 23:30

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