Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
27865910
DOI
10.1016/j.bbadis.2016.11.020
PII: S0925-4439(16)30302-7
Knihovny.cz E-resources
- Keywords
- Aggregation, Alzheimer's disease, Amyloid, Aβ peptide, Muscarinic/nicotinic acetylcholine receptor antagonist, N-Methyl-d-aspartate receptor antagonist, β-Secretase inhibitor,
- MeSH
- Alzheimer Disease drug therapy metabolism MeSH
- Amantadine analogs & derivatives pharmacology MeSH
- Amyloid beta-Peptides antagonists & inhibitors metabolism MeSH
- CHO Cells MeSH
- Cholinesterases metabolism MeSH
- Molecular Targeted Therapy MeSH
- Cricetulus MeSH
- Dimerization MeSH
- HEK293 Cells MeSH
- Enzyme Inhibitors chemistry pharmacology MeSH
- Humans MeSH
- Receptor, Muscarinic M1 antagonists & inhibitors metabolism MeSH
- Receptors, Cholinergic metabolism MeSH
- Receptors, N-Methyl-D-Aspartate metabolism MeSH
- Amyloid Precursor Protein Secretases antagonists & inhibitors metabolism MeSH
- Tacrine analogs & derivatives chemistry pharmacology MeSH
- Xenopus MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 7-methoxytacrine MeSH Browser
- Amantadine MeSH
- Amyloid beta-Peptides MeSH
- Cholinesterases MeSH
- Enzyme Inhibitors MeSH
- Receptor, Muscarinic M1 MeSH
- Receptors, Cholinergic MeSH
- Receptors, N-Methyl-D-Aspartate MeSH
- Amyloid Precursor Protein Secretases MeSH
- Tacrine MeSH
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the "one-molecule-one-target" paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory. The spectroscopic, microscopic and cell culture methods were used for systematic investigation of the interference of the heterodimers with β-secretase (BACE1) activity, Aβ peptide amyloid fibrillization (amyloid theory) and interaction with M1 subtype of muscarinic (mAChRs), nicotinic (nAChRs) acetylcholine receptors (cholinergic theory) and N-methyl-d-aspartate receptors (NMDA) (glutamatergic theory). The drug-like properties of selected compounds have been evaluated from the point of view of blood-brain barrier penetration and cell proliferation. We have confirmed the multipotent effect of novel series of compounds. They inhibited effectively Aβ peptide amyloid fibrillization and affected the BACE1 activity. Moreover, they have AChE inhibitory potency but they could not potentiate cholinergic transmission via direct interaction with cholinergic receptors. All compounds were reported to act as an antagonist of both M1 muscarinic and muscle-type nicotinic receptors. We have found that 7-methoxytacrine - memantine heterodimers are able to hit multiple targets associated with Alzheimer's disease and thus, have a potential clinical impact for slowing or blocking the neurodegenerative process related to this disease.
References provided by Crossref.org
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