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|Title: ||THE ROLE OF CHOLINESTERASES IN ALZHEIMER’S DISEASE: SCREENING OF TARGET COMPOUNDS|
|Authors: ||Bacalhau, P.|
San Juan, A.
Caldeira, A. T.
Martins, M. R.
|Editors: ||Nitsch, R.M.|
|Keywords: ||Alzheimer's disease|
|Issue Date: ||Mar-2015|
|Publisher: ||Karger, Medical and Scietif publishions.|
|Citation: ||P. Bacalhau , A. San Juan , C. Marques , D. Peixoto , A. Burke , A. Caldeira , M.R. Martins (205) The role of cholinesterases in Alzheimer’s disease: screening of target compounds. Neurodegenerative Diseases, 15(1): pp 741. e-ISBN: 978-3-318-05023-3. DOI:10.1159/000381736|
|Abstract: ||Background: Alzheimer's disease (AD) is the most common form of dementia and
causes a progressive and irreversible neurodegeneration. The loss of cholinergic
neurons leads to the progressive reduction of acetylcholine (ACh) in the brain and
resulting cognitive impairment in AD. ACh is hydrolyzed by both acetylcholinesterase
(AChE) and butirylcholinesterase (BuChE). It was found that in the course of the
disease, levels of AChE in the central nervous system (CNS) decrease, inversely to
BuChE levels, so both enzymes represent legitimate therapeutic targets for ameliorating the cholinergic deficit characteristic of AD.
Objective: Screen a library of new isoquinoline, indolinone and benzoazepinone
derivatives for their ability to inhibit AChE and BuChE activities, using galantamine and rivastigmine as standards.
Methods: The enzyme activities and inhibition studies were carried out using
spectrophotometric techniques, based on the Ellman’s method, with acetylthiocholine
(ATCI) and butirylthiocholine (BTCI) as substrates, for AChE and BuChE, respectively.
The data were complemented with modeling to analyze the structure-activity
Results: Our results show that the tested compounds are competitive inhibitors for
AChEs and BuChEs, as the benchmarks galantamine and rivastigmine. The isoquinoline and indolinone derivative compounds showed strong anti-cholinesterases activities, with
IC50 values ranging from 0.4 to 400 micromolar.
Conclusions: The results presented are promising and provide a pathway for the design of new AChE and BuChE inhibitors.|
|Appears in Collections:||HERCULES - Publicações - Artigos em Revistas Internacionais Com Arbitragem Científica|
MED - Publicações - Artigos em Revistas Internacionais Com Arbitragem Científica
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