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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Detalles Bibliográficos
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
Descripción
Sumario: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.

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