Multidirectional in vitro and in cellulo studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer's disease.
J Enzyme Inhib Med Chem
; 35(1): 1944-1952, 2020 Dec.
Article
in En
| MEDLINE
| ID: mdl-33092411
ABSTRACT
Effective therapy of Alzheimer's disease (AD) requires treatment with a combination of drugs that modulate various pathomechanisms contributing to the disease. In our research, we have focused on the development of multi-target-directed ligands - 5-HT6 receptor antagonists and cholinesterase inhibitors - with disease-modifying properties. We have performed extended in vitro (FRET assay) and in cellulo (Escherichia coli model of protein aggregation) studies on their ß-secretase, tau, and amyloid ß aggregation inhibitory activity. Within these multifunctional ligands, we have identified compound 17 with inhibitory potency against tau and amyloid ß aggregation in in cellulo assay of 59% and 56% at 10 µM, respectively, hBACE IC50=4 µM, h5TH6 K i=94 nM, hAChE IC50=26 nM, and eqBuChE IC50=5 nM. This study led to the development of multifunctional ligands with a broad range of biological activities crucial not only for the symptomatic but also for the disease-modifying treatment of AD.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cholinesterase Inhibitors
/
Cholinesterases
/
Amyloid beta-Peptides
/
Receptors, Serotonin
/
Tau Proteins
/
Alzheimer Disease
Type of study:
Diagnostic_studies
/
Etiology_studies
Limits:
Humans
Language:
En
Journal:
J Enzyme Inhib Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2020
Document type:
Article
Affiliation country:
Poland