Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F17%3A10336918" target="_blank" >RIV/00179906:_____/17:10336918 - isvavai.cz</a>

Alternative codes found

RIV/67985823:_____/17:00474014 RIV/60162694:G44__/17:43875725

Result on the web

<a href="http://dx.doi.org/10.1016/j.bbadis.2016.11.020" target="_blank" >http://dx.doi.org/10.1016/j.bbadis.2016.11.020</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bbadis.2016.11.020" target="_blank" >10.1016/j.bbadis.2016.11.020</a>

Result language

angličtina

Original language name

Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment

Original language description

Alzheimer&apos;s disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the &quot;one-molecule-one-target&quot; 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 beta-secretase (BACE1) activity, A beta 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 A beta 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&apos;s disease and thus, have a potential clinical impact for slowing or blocking the neurodegenerative process related to this disease.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30104 - Pharmacology and pharmacy

Project

<a href="/en/project/GA16-08554S" target="_blank" >GA16-08554S: Novel hybrid compounds in the cognitive decline caused by neurodegeneration</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Biochimica et Biophysica Acta - Molecular Basis of Disease

ISSN

0925-4439

e-ISSN

—

Volume of the periodical

1863

Issue of the periodical within the volume

2

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

13

Pages from-to

607-619

UT code for WoS article

000392779800025

EID of the result in the Scopus database

2-s2.0-85005965823