Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease

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 synt...

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Autores: 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, 1964-, Vázquez Cruz, Santiago
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/194421
Acceso en línea:https://hdl.handle.net/2445/194421
Access Level:acceso abierto
Palabra clave:Malaltia d'Alzheimer
Nanopartícules
Química farmacèutica
Alzheimer's disease
Nanoparticles
Pharmaceutical chemistry
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spelling Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's diseaseTurcu, Andreea L.Companys Alemany, JúliaPhillips, Matthew B.Patel, Dhilon S.Griñán Ferré, ChristianLoza, María IsabelBrea, JoséPérez, BelénSoto del Cerro, DavidSureda, Francesc X.Kurnikova, Maria G.Johnson, Jon W.Pallàs i Llibería, Mercè, 1964-Vázquez Cruz, SantiagoMalaltia d'AlzheimerNanopartículesQuímica farmacèuticaAlzheimer's diseaseNanoparticlesPharmaceutical chemistryCurrently, 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.Elsevier Masson SAS2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/194421Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.ejmech.2022.114354European Journal of Medicinal Chemistry, 2022, vol. 236, p. 114354https://doi.org/10.1016/j.ejmech.2022.114354cc by-nc-nd (c) Andreea L. Turcu, et al., 2022http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1944212026-05-27T06:46:51Z
dc.title.none.fl_str_mv Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease
title Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease
spellingShingle Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease
Turcu, Andreea L.
Malaltia d'Alzheimer
Nanopartícules
Química farmacèutica
Alzheimer's disease
Nanoparticles
Pharmaceutical chemistry
title_short Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease
title_full Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease
title_fullStr Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease
title_full_unstemmed Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease
title_sort Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease
dc.creator.none.fl_str_mv 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, 1964-
Vázquez Cruz, Santiago
author Turcu, Andreea L.
author_facet 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, 1964-
Vázquez Cruz, Santiago
author_role author
author2 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, 1964-
Vázquez Cruz, Santiago
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malaltia d'Alzheimer
Nanopartícules
Química farmacèutica
Alzheimer's disease
Nanoparticles
Pharmaceutical chemistry
topic Malaltia d'Alzheimer
Nanopartícules
Química farmacèutica
Alzheimer's disease
Nanoparticles
Pharmaceutical chemistry
description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/194421
url https://hdl.handle.net/2445/194421
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.ejmech.2022.114354
European Journal of Medicinal Chemistry, 2022, vol. 236, p. 114354
https://doi.org/10.1016/j.ejmech.2022.114354
dc.rights.none.fl_str_mv cc by-nc-nd (c) Andreea L. Turcu, et al., 2022
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Andreea L. Turcu, et al., 2022
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier Masson SAS
publisher.none.fl_str_mv Elsevier Masson SAS
dc.source.none.fl_str_mv Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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