| Literature DB >> 29384656 |
Anna Więckowska, Tomasz Wichur, Justyna Godyń, Adam Bucki, Monika Marcinkowska, Agata Siwek, Krzysztof Więckowski, Paula Zaręba, Damijan Knez1, Monika Głuch-Lutwin, Grzegorz Kazek, Gniewomir Latacz, Kamil Mika, Marcin Kołaczkowski, Jan Korabecny2,3, Ondrej Soukup2,3, Marketa Benkova2,3, Katarzyna Kieć-Kononowicz, Stanislav Gobec1, Barbara Malawska.
Abstract
Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid β antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors ( Ki = 18 nM) and noncompetitive inhibitor of cholinesterases (IC50 hAChE = 14 nM, IC50 eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid β antiaggregation activity (IC50 = 1.27 μM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.Entities:
Keywords: 5-HT6 receptor antagonists; Alzheimer’s disease; acetylcholinesterase inhibitors; butyrylcholinesterase inhibitors; inhibition of β-amyloid aggregation; multitarget-directed ligands
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Year: 2018 PMID： 29384656 DOI： 10.1021/acschemneuro.8b00024
Source DB: PubMed Journal: ACS Chem Neurosci ISSN： 1948-7193 Impact factor: 4.418