期刊
ACS CHEMICAL NEUROSCIENCE
卷 9, 期 5, 页码 1195-1214出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.8b00024
关键词
Alzheimer's disease; multitarget-directed ligands; acetylcholinesterase inhibitors; butyrylcholinesterase inhibitors; 5-HT6 receptor antagonists; inhibition of beta-amyloid aggregation
资金
- Polish Ministry for Science and Higher Education [IP2012063272]
- National Science Centre Poland [2016/23/D/NZ7/01328]
- Jagiellonian University Medical College [K/ZDS/007216]
- Slovenian Research Agency [P1-0208, L1-8157]
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-HT(6 )receptors, acetyl/butyrylcholinesterase inhibition, and amyloid beta antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT(6 )receptors (K-i= 18 nM) and noncompetitive inhibitor of cholinesterases (IC50hAChE = 14 nM, IC50eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid beta antiaggregation activity (IC50 = 1.27 mu M) 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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