Memantine Derivatives As Multitarget Agents in Alzheimer's Disease

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2020 Sep 5

PMID 32887400

Citations 13

Authors

Giambattista Marotta

Filippo Basagni

Michela Rosini

Anna Minarini

Affiliations

Soon will be listed here.

Abstract

Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer's disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors.

Citing Articles

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References

Kumamoto T, Nakajima M, Uga R, Ihayazaka N, Kashihara H, Katakawa K . Design, synthesis, and evaluation of polyamine-memantine hybrids as NMDA channel blockers. Bioorg Med Chem. 2017; 26(3):603-608. DOI: 10.1016/j.bmc.2017.12.021. View

Li Q, Yang H, Chen Y, Sun H . Recent progress in the identification of selective butyrylcholinesterase inhibitors for Alzheimer's disease. Eur J Med Chem. 2017; 132:294-309. DOI: 10.1016/j.ejmech.2017.03.062. View

Horak M, Holubova K, Nepovimova E, Krusek J, Kaniakova M, Korabecny J . The pharmacology of tacrine at N-methyl-d-aspartate receptors. Prog Neuropsychopharmacol Biol Psychiatry. 2017; 75:54-62. DOI: 10.1016/j.pnpbp.2017.01.003. View

Reggiani A, Simoni E, Caporaso R, Meunier J, Keller E, Maurice T . In Vivo Characterization of ARN14140, a Memantine/Galantamine-Based Multi-Target Compound for Alzheimer's Disease. Sci Rep. 2016; 6:33172. PMC: 5016838. DOI: 10.1038/srep33172. View

Rosini M, Simoni E, Minarini A, Melchiorre C . Multi-target design strategies in the context of Alzheimer's disease: acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces. Neurochem Res. 2014; 39(10):1914-23. DOI: 10.1007/s11064-014-1250-1. View

Parsons C, Danysz W, Dekundy A, Pulte I . Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease. Neurotox Res. 2013; 24(3):358-69. PMC: 3753463. DOI: 10.1007/s12640-013-9398-z. View

Gazova Z, Soukup O, Sepsova V, Siposova K, Drtinova L, Jost P . Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment. Biochim Biophys Acta Mol Basis Dis. 2016; 1863(2):607-619. DOI: 10.1016/j.bbadis.2016.11.020. View

Pieper A, McKnight S, Ready J . P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases. Chem Soc Rev. 2014; 43(19):6716-26. PMC: 4237066. DOI: 10.1039/c3cs60448a. View

McGehee D, Heath M, Gelber S, Devay P, Role L . Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science. 1995; 269(5231):1692-6. DOI: 10.1126/science.7569895. View

10.

Ono K, Hirohata M, Yamada M . Alpha-lipoic acid exhibits anti-amyloidogenicity for beta-amyloid fibrils in vitro. Biochem Biophys Res Commun. 2006; 341(4):1046-52. DOI: 10.1016/j.bbrc.2006.01.063. View

11.

Gancar M, Ho K, Abdul Mohid S, Thai N, Bednarikova Z, Nguyen H . 7-Methoxytacrine and 2-Aminobenzothiazole Heterodimers: Structure-Mechanism Relationship of Amyloid Inhibitors Based on Rational Design. ACS Chem Neurosci. 2020; 11(5):715-729. DOI: 10.1021/acschemneuro.9b00419. View

12.

Kaniakova M, Nepovimova E, Kleteckova L, Skrenkova K, Holubova K, Chrienova Z . Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer's Disease. Curr Alzheimer Res. 2019; 16(9):821-833. DOI: 10.2174/1567205016666190228122218. View

13.

Choubdar N, Golshani M, Jalili-Baleh L, Nadri H, Kucukkilinc T, Ayazgok B . New classes of carbazoles as potential multi-functional anti-Alzheimer's agents. Bioorg Chem. 2019; 91:103164. DOI: 10.1016/j.bioorg.2019.103164. View

14.

Basagni F, Lanni C, Minarini A, Rosini M . Lights and shadows of electrophile signaling: focus on the Nrf2-Keap1 pathway. Future Med Chem. 2019; 11(7):707-721. DOI: 10.4155/fmc-2018-0423. View

15.

Kodis E, Choi S, Swanson E, Ferreira G, Bloom G . N-methyl-D-aspartate receptor-mediated calcium influx connects amyloid-β oligomers to ectopic neuronal cell cycle reentry in Alzheimer's disease. Alzheimers Dement. 2018; 14(10):1302-1312. PMC: 8363206. DOI: 10.1016/j.jalz.2018.05.017. View

16.

Rosini M . Polypharmacology: the rise of multitarget drugs over combination therapies. Future Med Chem. 2014; 6(5):485-7. DOI: 10.4155/fmc.14.25. View

17.

Parsons M, Raymond L . Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron. 2014; 82(2):279-93. DOI: 10.1016/j.neuron.2014.03.030. View

18.

Ghobadian R, Nadri H, Moradi A, Bukhari S, Mahdavi M, Asadi M . Design, synthesis, and biological evaluation of selective and potent Carbazole-based butyrylcholinesterase inhibitors. Bioorg Med Chem. 2018; 26(17):4952-4962. DOI: 10.1016/j.bmc.2018.08.035. View

19.

Li Q, He S, Chen Y, Feng F, Qu W, Sun H . Donepezil-based multi-functional cholinesterase inhibitors for treatment of Alzheimer's disease. Eur J Med Chem. 2018; 158:463-477. DOI: 10.1016/j.ejmech.2018.09.031. View

20.

Perez-Areales F, Turcu A, Barniol-Xicota M, Pont C, Pivetta D, Espargaro A . A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors. Eur J Med Chem. 2019; 180:613-626. DOI: 10.1016/j.ejmech.2019.07.051. View