Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/194421
Title: | Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease |
Author: | Turcu, Andreea L. Companys Alemany, Júlia Phillips, Matthew B. Patel, Dhilon S. Griñán Ferré, Christian Loza, María Isabel Brea, José Pérez, Belén Soto del Cerro, David Sureda, Francesc X. Kurnikova, Maria G. Johnson, Jon W. Pallàs i Llibería, Mercè Vázquez Cruz, Santiago |
Keywords: | Malaltia d'Alzheimer Nanopartícules Química farmacèutica Alzheimer's disease Nanoparticles Pharmaceutical chemistry |
Issue Date: | 5-Jun-2022 |
Publisher: | Elsevier Masson SAS |
Abstract: | Currently, of the few accessible symptomatic therapies for Alzheimer's disease (AD), memantine is the only N-methyl-d-aspartate receptor (NMDAR) blocker approved by the FDA. This work further explores a series of memantine analogs featuring a benzohomoadamantane scaffold. Most of the newly synthesized compounds block NMDARs in the micromolar range, but with lower potency than previously reported hit IIc, results that were supported by molecular dynamics simulations. Subsequently, electrophysiological studies with the more potent compounds allowed classification of IIc, a low micromolar, uncompetitive, voltage-dependent, NMDAR blocker, as a memantine-like compound. The excellent in vitro DMPK properties of IIc made it a promising candidate for in vivo studies in Caenorhabditis elegans (C. elegans) and in the 5XFAD mouse model of AD. Administration of IIc or memantine improved locomotion and rescues chemotaxis behavior in C. elegans. Furthermore, both compounds enhanced working memory in 5XFAD mice and modified NMDAR and CREB signaling, which may prevent synaptic dysfunction and modulate neurodegenerative progression. |
Note: | Reproducció del document publicat a: https://doi.org/10.1016/j.ejmech.2022.114354 |
It is part of: | European Journal of Medicinal Chemistry, 2022, vol. 236, p. 114354 |
URI: | http://hdl.handle.net/2445/194421 |
Related resource: | https://doi.org/10.1016/j.ejmech.2022.114354 |
ISSN: | 0223-5234 |
Appears in Collections: | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) Articles publicats en revistes (Biomedicina) Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia) |
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