Turcu, Andreea L.Companys Alemany, JúliaPhillips, Matthew B.Patel, Dhilon S.Griñán Ferré, ChristianLoza García, María IsabelBrea Floriani, José ManuelPérez, BelénSoto, DavidSureda, Francesc X.Kurnikova, Maria G.Johnson, Jon W.Pallàs, MercèVázquez, Santiago2026-01-132026-01-132022-04-08Andreea L. Turcu, Júlia Companys-Alemany, Matthew B. Phillips, Dhilon S. Patel, Christian Griñán-Ferré, M. Isabel Loza, José M. Brea, Belén Pérez, David Soto, Francesc X. Sureda, Maria G. Kurnikova, Jon W. Johnson, Mercè Pallàs, Santiago Vázquez, Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease, European Journal of Medicinal Chemistry, Volume 236, 2022, 114354, ISSN 0223-5234, https://doi.org/10.1016/j.ejmech.2022.114354https://hdl.handle.net/10347/45096Currently, 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 progressioneng© 2022 The Authors. Published by Elsevier Masson SAS. This article is available under the Creative Commons CC-BY-NC-ND licenseAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Alzheimer's diseaseBenzohomoadamantaneCaenorhabditis elegansElectrophysiology5XFADMemantine analogsjournal article10.1016/j.ejmech.2022.1143541768-3254open access