Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease
Year: 2022
Type: article
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.
Institutions: Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, University of Pittsburgh, Carnegie Mellon University, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases, Universitat Autònoma de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat Rovira i Virgili, Consejo Superior de Investigaciones Científicas
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,570
Funders: National Science Foundation, Universitat de Barcelona, Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España, Xunta de Galicia, National Institutes of Health, Agència de Gestió d'Ajuts Universitaris i de Recerca, European Regional Development Fund, Agencia Estatal de Investigación, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: G128883266, G1496055848, G165958228, G1701151990, G1958862459, G2206590661, G2238108805, G2673512141, G2731555168, G2844922136, G3013207569, G3022609761, G3469311880, G3480869486, G3694284866, XSEDE 2.0: Integrating, Enabling and Enhancing National Cyberinfrastructure with Expanding Community Involvement, G3876637791, G4256439867, G5080475149, G578634983, G585269259, G6204768751, G6590774998, Ca2+-Dependent Block by Mematine and Selective Inhibition of Overactive NMDA Receptors, G677621808, G6992098544, G7065702806, G7254984022, Structural determinants of Ca(2+)-dependent inhibition of NMDA receptors by memantine, G7493841644, G7970363070, G8584092977, G8684520763, G8838560759
OpenAlex ID: W4224284673