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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Published inEuropean journal of medicinal chemistry Vol. 236; p. 114354
Main Authors Turcu, Andreea L., Companys-Alemany, Júlia, Phillips, Matthew B., Patel, Dhilon S., Griñán-Ferré, Christian, Loza, M. Isabel, Brea, José M., Pérez, Belén, Soto, David, Sureda, Francesc X., Kurnikova, Maria G., Johnson, Jon W., Pallàs, Mercè, Vázquez, Santiago
Format Journal Article
LanguageEnglish
Published France Elsevier Masson SAS 05.06.2022
Subjects
5XFAD
Alzheimer Disease - drug therapy
Alzheimer's disease
Animals
Benzohomoadamantane
Caenorhabditis elegans
Disease Models, Animal
Electrophysiology
Memantine - pharmacology
Memantine analogs
Mice
Receptors, N-Methyl-D-Aspartate
Benzohomoadamantane
Electrophysiology
Caenorhabditis elegans
Memantine analogs
5XFAD
Alzheimer's disease
Online AccessGet full text
ISSN0223-5234
1768-3254
1768-3254
DOI10.1016/j.ejmech.2022.114354

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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. [Display omitted] •Several benzohomoadamantane-based amines were synthesized.•The compounds were evaluated as blockers of the NMDA receptor.•A previously reported compound was as potent as the clinically approved memantine.•Electrophysiological characterization of a selected amine was carried out.•The selected amine showed positive effects in in vivo models of Alzheimer's disease.
AbstractList 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.
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.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.
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.
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. [Display omitted] •Several benzohomoadamantane-based amines were synthesized.•The compounds were evaluated as blockers of the NMDA receptor.•A previously reported compound was as potent as the clinically approved memantine.•Electrophysiological characterization of a selected amine was carried out.•The selected amine showed positive effects in in vivo models of Alzheimer's disease.
ArticleNumber 114354
Author Pérez, Belén
Sureda, Francesc X.
Loza, M. Isabel
Kurnikova, Maria G.
Phillips, Matthew B.
Griñán-Ferré, Christian
Companys-Alemany, Júlia
Turcu, Andreea L.
Vázquez, Santiago
Soto, David
Brea, José M.
Johnson, Jon W.
Pallàs, Mercè
Patel, Dhilon S.
AuthorAffiliation 6 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
8 August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
9 Pharmacology Unit, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, C./ St. Llorenç 21, 43201 Reus, Tarragona, Spain
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
7 Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, E-08193 Bellaterra, Spain
3 Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neurosciences (NeuroUB), Universitat de Barcelona, Av. Joan
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Keywords Benzohomoadamantane
Electrophysiology
Caenorhabditis elegans
Memantine analogs
5XFAD
Alzheimer's disease
Language English
License This is an open access article under the CC BY-NC-ND license.
Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
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content type line 23
A.L.T. and J.C.-A. contributed equally. S.V. conceived the idea. A.L.T synthesized and chemically characterized the compounds. F.X.S. performed the intracellular calcium-based determination of the IC50s in cells. A.L.T., M.B.P., D.S. and J.W.J. designed and carried out electrophysiological studies. D.S.P. and M.G.K designed and performed MD calculations. M.I.L., J.M.B. and B.P. carried out DMPK studies. J.C.-A., C.G.-F. and M.P. designed and carried out the in vivo experiments. A.L.T. wrote the first draft of the manuscript. A.L.T., D.S., M.B.P, J.W.J, D.S.P, M.G.K., J.C.-A, C.G.-F, M.P. and S.V. wrote the definitive manuscript with feedback from all the authors. All authors have given approval to the final version of the manuscript.
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Snippet Currently, of the few accessible symptomatic therapies for Alzheimer's disease (AD), memantine is the only N-methyl-d-aspartate receptor (NMDAR) blocker...
Currently, of the few accessible symptomatic therapies for Alzheimer’s disease (AD), memantine is the only N -methyl- D -aspartate receptor (NMDAR) blocker...
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SubjectTerms 5XFAD
Alzheimer Disease - drug therapy
Alzheimer's disease
Animals
Benzohomoadamantane
Caenorhabditis elegans
Disease Models, Animal
Electrophysiology
Memantine - pharmacology
Memantine analogs
Mice
Receptors, N-Methyl-D-Aspartate
Title Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer's disease
URI https://dx.doi.org/10.1016/j.ejmech.2022.114354
https://www.ncbi.nlm.nih.gov/pubmed/35453065
https://www.proquest.com/docview/2654291567
https://pubmed.ncbi.nlm.nih.gov/PMC9106868
Volume 236
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