1. Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease
- Author
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Tomasz Wichur, Anna Więckowska, Agata Siwek, Ondrej Soukup, Jan Korabecny, Stanislav Gobec, Monika Marcinkowska, Monika Głuch-Lutwin, Paula Zaręba, Kamil Mika, Grzegorz Kazek, Katarzyna Kieć-Kononowicz, Marketa Benkova, Krzysztof Więckowski, Marcin Kołaczkowski, Adam Bucki, Barbara Malawska, Gniewomir Latacz, Damijan Knez, and Justyna Godyń
- Subjects
0301 basic medicine ,Models, Molecular ,Physiology ,Cognitive Neuroscience ,Pharmacology ,Ligands ,Biochemistry ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Non-competitive inhibition ,Alzheimer Disease ,medicine ,Structure–activity relationship ,Humans ,Receptor ,Butyrylcholinesterase ,Cholinesterase ,Amyloid beta-Peptides ,biology ,Chemistry ,Antagonist ,Cell Biology ,General Medicine ,medicine.disease ,Peptide Fragments ,Molecular Docking Simulation ,030104 developmental biology ,Drug Design ,biology.protein ,Cholinesterase Inhibitors ,Alzheimer's disease ,Pharmacophore ,030217 neurology & neurosurgery - 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.
- Published
- 2018