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

Kód výsledku v 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>

Nalezeny alternativní kódy

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

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GA16-08554S" target="_blank" >GA16-08554S: Nové hybridní molekuly v léčbě kognitivních poruch spojených s neurodegenerací</a><br>

Návaznosti

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

Rok uplatnění

2017

Kód důvěrnosti údajů

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

Název periodika

Biochimica et Biophysica Acta - Molecular Basis of Disease

ISSN

0925-4439

e-ISSN

—

Svazek periodika

1863

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

13

Strana od-do

607-619

Kód UT WoS článku

000392779800025

EID výsledku v databázi Scopus

2-s2.0-85005965823