Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer's Disease
Language English Country United Arab Emirates Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
30819076
DOI
10.2174/1567205016666190228122218
PII: CAR-EPUB-96943
Knihovny.cz E-resources
- Keywords
- 6-Chlorotacrine, Alzheimer´s disease, NMDA receptor, acetylcholinesterase, ion channel, memantine, patch-clamp technique.,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Alzheimer Disease drug therapy metabolism MeSH
- CHO Cells MeSH
- Cholinesterase Inhibitors chemical synthesis pharmacology MeSH
- Cricetulus MeSH
- HEK293 Cells MeSH
- Blood-Brain Barrier drug effects metabolism MeSH
- Capillary Permeability MeSH
- Glutamic Acid metabolism MeSH
- Humans MeSH
- Ligands MeSH
- Memantine chemical synthesis pharmacology MeSH
- Neuroprotective Agents chemical synthesis pharmacology MeSH
- Rats, Wistar MeSH
- Receptors, N-Methyl-D-Aspartate antagonists & inhibitors metabolism MeSH
- Molecular Docking Simulation MeSH
- Tacrine analogs & derivatives chemical synthesis pharmacology MeSH
- Tissue Culture Techniques MeSH
- Cell Survival drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 6-chlorotacrine MeSH Browser
- Acetylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Glutamic Acid MeSH
- Ligands MeSH
- Memantine MeSH
- Neuroprotective Agents MeSH
- Receptors, N-Methyl-D-Aspartate MeSH
- Tacrine MeSH
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called "multi-targeting" approach has been established. OBJECTIVES: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. METHODS: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. RESULTS: A novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. CONCLUSION: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.
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