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Review
. 2020 Sep 2;25(17):4005.
doi: 10.3390/molecules25174005.

Memantine Derivatives as Multitarget Agents in Alzheimer's Disease

Giambattista Marotta  1 , Filippo Basagni  1 , Michela Rosini  1 , Anna Minarini  1
Affiliations
Review

Memantine Derivatives as Multitarget Agents in Alzheimer's Disease

Giambattista Marotta et al. Molecules. .

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.

Keywords: Alzheimer’s disease; hybrid structures; memantine; multi target directed ligand.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Conjugation strategies exploiting memantine’s NMDAR antagonism to tackle AD.
Figure 2
Figure 2
Drug design and biological activities of 7-MEOTA-amantadine hybrids 1 and 2.
Figure 3
Figure 3
Drug design and biological activities of 6-chlorotacrine-memantine hybrid 3.
Figure 4
Figure 4
Drug design and biological activities of 6-chlorotacrine-benzohomoadamantane hybrids 4–6.
Figure 5
Figure 5
Drug design and biological activities of memantine-galantamine hybrids 7 and 8.
Figure 6
Figure 6
Drug design and biological activities of carbazole/tetrahydrocarbazole-aminoadamantane hybrids 9–11.
Figure 7
Figure 7
Drug design and biological activities of ferulic acid-memantine hybrid 12.
Figure 8
Figure 8
Drug design and biological activities of lipoic acid-memantine hybrid 13.
Figure 9
Figure 9
Drug design and biological activities of propargyl-amantadine hybrids 14 and 15.
Figure 10
Figure 10
Drug design and biological activities of polyamine-memantine hybrids 16 and 17.
Figure 11
Figure 11
Drug design and biological activities of memantine prodrug 18.
Figure 12
Figure 12
Drug design and biological activities of N’-arylcarbohydrazide-aminoadamantane hybrid 19.
See this image and copyright information in PMC

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