Articles producció científica> Ciències Mèdiques Bàsiques

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

  • Identification data

    Identifier: imarina:9262040
    Authors:
    Turcu ALCompanys-Alemany JPhillips MBPatel DSGriñán-Ferré CLoza MIBrea JMPérez BSoto DSureda FXKurnikova MGJohnson JWPallàs MVázquez S
    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.
  • Others:

    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: 2024-09-07
    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: https://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
  • Keywords:

    Chemistry, Medicinal,Drug Discovery,Medicine (Miscellaneous),Organic Chemistry,Pharmacology
    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
    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
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