Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
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.

PubMed Disclaimer

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

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Parsons M.P., Raymond L.A. Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron. 2014;82:279–293. doi: 10.1016/j.neuron.2014.03.030. - DOI - PubMed
    1. Léveillé F., El Gaamouch F., Gouix E., Lecocq M., Lobner D., Nicole O., Buisson A. Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J. 2008;22:4258–4271. doi: 10.1096/fj.08-107268. - DOI - PubMed
    1. Folch J., Busquets O., Ettcheto M., Sánchez-López E., Castro-Torres R.D., Verdaguer E., Garcia M.L., Olloquequi J., Casadesús G., Beas-Zarate C., et al. Memantine for the Treatment of Dementia: A Review on its Current and Future Applications. J. Alzheimer’s Dis. 2018;62:1223–1240. doi: 10.3233/JAD-170672. - DOI - PMC - PubMed
    1. Xia P., Chen H.S., Zhang D., Lipton S.A. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J. Neurosci. 2010;30:11246–11250. doi: 10.1523/JNEUROSCI.2488-10.2010. - DOI - PMC - PubMed
    1. Lipton S.A. Pathologically activated therapeutics for neuroprotection. Nat. Rev. Neurosci. 2007;8:803–808. doi: 10.1038/nrn2229. - DOI - PubMed