Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer’s disease
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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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Memantine is safe and well-tolerated and is used to treat moderate-to-severe AD alone or in combination with AChEI.
“Memantine is safe and well-tolerated; it is used to treat moderate-to-severe AD alone or in combination with AChEI [124,125,126].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [125]
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- Authors
- Turcu, A. L., Companys-Alemany, J., Phillips, M. B., Patel, D. S., Griñán-Ferré, C., Loza, M. I., Brea, J. M., Pérez, B., Soto, D., Sureda, F. X., Kurnikova, M. G., Johnson, J. W., Pallàs, M., & Vázquez, S.
- Affiliations
- Institut de Biomedicina de la Universitat de Barcelona (ES)
- University of Pittsburgh (US)
- Carnegie Mellon University (US)
- Universitat Autònoma de Barcelona (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Universitat Rovira i Virgili (ES)
- Universitat de Barcelona (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- Vázquez, Santiago
- ORCID
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 236
- Pages
- 114354
- ISSN
- 0223-5234 (ISSN-L)
- PMC
- PMC9106868
- OpenAlex
- W4224284673
- Cited by
- 27
- References
- 110
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 9 · 2023: 5 · 2022: 5
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Journal of Medicinal Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rovira & Virgili repository (submittedVersion, cc-by)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by-nc-nd)
- Hispana (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation (1548562)
- Universitat de Barcelona (MDM-2017-0729)
- Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España (PID2019-106285RB-I00, PID2019-106285RB, SAF2017-82771-R, MDM‐2017‐0729, SAF2017-82771, 2017SGR106)
- Xunta de Galicia (ED431C, ED431G 2019/02, ED431C 2018, ED431G, PID2019-106285RB, 2017SGR106)
- National Institutes of Health (ACI-1548562)
- Agència de Gestió d'Ajuts Universitaris i de Recerca (PID2019-106285RB, 2017-SGR-106, SAF2017-82771-R)
- European Regional Development Fund (ED431G 2019/02, 2017SGR106, PID2019, SAF2017-82771-R, SAF2017, ED431C, MDM-2017-0729, PID2019-106285RB)
- Agencia Estatal de Investigación (2017SGR106, 13039, 10.13039, SAF2017-82771-R, PID2019-106285RB, PID2019)
- National Institute on Aging (R01AG065594)
- National Institute of Neurological Disorders and Stroke (F31NS113477)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, NMDA receptor antagonists, Caenorhabditis elegans, 5xFAD mice, locomotion, chemotaxis, working memory, CREB signaling, synaptic dysfunction, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Memantine, Receptors, N-Methyl-D-Aspartate, Caenorhabditis elegans, Mice
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