Author, as appears in the article.: Turcu AL; Companys-Alemany J; Phillips MB; Patel DS; Griñán-Ferré C; Loza MI; Brea JM; Pérez B; Soto D; Sureda FX; Kurnikova MG; Johnson JW; Pallàs M; Vázquez S
Department: Ciències Mèdiques Bàsiques
URV's Author/s: Sureda Batlle, Francesc Xavier
Keywords: Nmda receptor antagonist Memantine analogs Electrophysiology Caenorhabditis elegans Benzohomoadamantane Alzheimer's disease 5xfad software news patch-clamp mouse model molecular-dynamics memantine analogs glutamate electrophysiology drug channel block caenorhabditis elegans benzohomoadamantane amantadine aducanumab 5xfad
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.
Thematic Areas: Zootecnia / recursos pesqueiros Saúde coletiva Química Pharmacology Organic chemistry Odontología Nutrição Medicine (miscellaneous) Medicina veterinaria Medicina iii Medicina ii Medicina i Materiais Interdisciplinar Farmacia Ensino Engenharias iv Engenharias ii Enfermagem Educação física Drug discovery Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciências agrárias i Ciência de alimentos Ciência da computação Chemistry, medicinal Biotecnología Biodiversidade Astronomia / física
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: francesc.sureda@urv.cat
Author identifier: 0000-0002-7968-3929
Record's date: 2023-09-02
Papper version: info:eu-repo/semantics/publishedVersion
Link to the original source: https://www.sciencedirect.com/science/article/pii/S0223523422002562?via%3Dihub
Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: European Journal Of Medicinal Chemistry. 236 114354-
APA: Turcu AL; Companys-Alemany J; Phillips MB; Patel DS; Griñán-Ferré C; Loza MI; Brea JM; Pérez B; Soto D; Sureda FX; Kurnikova MG; Johnson JW; Pallàs M; (2022). Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease. European Journal Of Medicinal Chemistry, 236(), 114354-. DOI: 10.1016/j.ejmech.2022.114354
Article's DOI: 10.1016/j.ejmech.2022.114354
Entity: Universitat Rovira i Virgili
Journal publication year: 2022
Publication Type: Journal Publications
Repositori URV