Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- 5-HT6 receptor antagonists, Alzheimer’s disease, acetylcholinesterase inhibitors, butyrylcholinesterase inhibitors, inhibition of β-amyloid aggregation, multitarget-directed ligands,
- MeSH
- Alzheimer Disease drug therapy etiology MeSH
- Amyloid beta-Peptides metabolism MeSH
- Butyrylcholinesterase pharmacology MeSH
- Cholinesterase Inhibitors pharmacology MeSH
- Humans MeSH
- Ligands * MeSH
- Models, Molecular MeSH
- Peptide Fragments metabolism MeSH
- Drug Design MeSH
- Molecular Docking Simulation MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Amyloid beta-Peptides MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Ligands * MeSH
- Peptide Fragments MeSH
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.
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