Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer's Disease
Jazyk angličtina Země Spojené arabské emiráty Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
30819076
DOI
10.2174/1567205016666190228122218
PII: CAR-EPUB-96943
Knihovny.cz E-zdroje
- Klíčová slova
- 6-Chlorotacrine, Alzheimer´s disease, NMDA receptor, acetylcholinesterase, ion channel, memantine, patch-clamp technique.,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- CHO buňky MeSH
- cholinesterasové inhibitory chemická syntéza farmakologie MeSH
- Cricetulus MeSH
- HEK293 buňky MeSH
- hematoencefalická bariéra účinky léků metabolismus MeSH
- kapilární permeabilita MeSH
- kyselina glutamová metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- memantin chemická syntéza farmakologie MeSH
- neuroprotektivní látky chemická syntéza farmakologie MeSH
- potkani Wistar MeSH
- receptory N-methyl-D-aspartátu antagonisté a inhibitory metabolismus MeSH
- simulace molekulového dockingu MeSH
- takrin analogy a deriváty chemická syntéza farmakologie MeSH
- techniky tkáňových kultur MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 6-chlorotacrine MeSH Prohlížeč
- acetylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- kyselina glutamová MeSH
- ligandy MeSH
- memantin MeSH
- neuroprotektivní látky MeSH
- receptory N-methyl-D-aspartátu MeSH
- takrin 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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