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

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

  • Eur J Med Chem. 2022 Jun 5;236:114354. doi: 10.1016/j.ejmech.2022.114354.
Andreea L Turcu 1,  Júlia Companys-Alemany 2,  Matthew B Phillips 3,  Dhilon S Patel 4,  Christian Griñán-Ferré 2,  M Isabel Loza 5,  José M Brea 5,  Belén Pérez 6,  David Soto 7,  Francesc X Sureda 8,  Maria G Kurnikova 4,  Jon W Johnson 3,  Mercè Pallàs 2,  Santiago Vázquez 9
Affiliations

Affiliations

  • 1 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació i Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain; Neurophysiology Laboratory, Department of Biomedicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036, Barcelona, Spain.
  • 2 Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neurosciences (NeuroUB), Universitat de Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain.
  • 3 Department of Neuroscience and Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • 4 Chemistry Department, Carnegie Mellon University, 4400 Fifth Ave, Pittsburgh, PA, 15213, USA.
  • 5 Innopharma Screening Platform, Biofarma Research Group, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, Universidad de Santiago de Compostela, Edificio CIMUS, Av. Barcelona, S/N, E, 15706, Santiago de Compostela, Spain.
  • 6 Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, E-08193, Bellaterra, Spain.
  • 7 Neurophysiology Laboratory, Department of Biomedicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
  • 8 Pharmacology Unit, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, C./ St. Llorenç 21, 43201, Reus, Tarragona, Spain.
  • 9 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació i Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain. Electronic address: svazquez@ub.edu.
PMID: 35453065 DOI: 10.1016/j.ejmech.2022.114354
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.

Keywords

5XFAD; Alzheimer's disease; Benzohomoadamantane; Caenorhabditis elegans; Electrophysiology; Memantine analogs.

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