Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
27865910
DOI
10.1016/j.bbadis.2016.11.020
PII: S0925-4439(16)30302-7
Knihovny.cz E-zdroje
- Klíčová slova
- Aggregation, Alzheimer's disease, Amyloid, Aβ peptide, Muscarinic/nicotinic acetylcholine receptor antagonist, N-Methyl-d-aspartate receptor antagonist, β-Secretase inhibitor,
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amantadin analogy a deriváty farmakologie MeSH
- amyloidní beta-protein antagonisté a inhibitory metabolismus MeSH
- CHO buňky MeSH
- cholinesterasy metabolismus MeSH
- cílená molekulární terapie MeSH
- Cricetulus MeSH
- dimerizace MeSH
- HEK293 buňky MeSH
- inhibitory enzymů chemie farmakologie MeSH
- lidé MeSH
- receptor muskarinový M1 antagonisté a inhibitory metabolismus MeSH
- receptory cholinergní metabolismus MeSH
- receptory N-methyl-D-aspartátu metabolismus MeSH
- sekretasy antagonisté a inhibitory metabolismus MeSH
- takrin analogy a deriváty chemie farmakologie MeSH
- Xenopus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 7-methoxytacrine MeSH Prohlížeč
- amantadin MeSH
- amyloidní beta-protein MeSH
- cholinesterasy MeSH
- inhibitory enzymů MeSH
- receptor muskarinový M1 MeSH
- receptory cholinergní MeSH
- receptory N-methyl-D-aspartátu MeSH
- sekretasy MeSH
- takrin 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.
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