New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer's disease
| Autor: | Marat A. Mukhamedyarov, Vyacheslav E. Semenov, Florian Nachon, José A. Dias, Tatiana N. Pashirova, L. F. Nurullin, Vasiliy M. Babaev, Patrick Masson, Victor I. Ilyin, Natalia Petrova, Sofya V. Lushchekina, Irina V. Zueva, Konstantin A. Petrov, Lucia Ya. Zakharova |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mice Transgenic CHO Cells Pharmacology Neuroprotection Mice Random Allocation 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound Cricetulus 0302 clinical medicine Drug Development Alzheimer Disease Cricetinae medicine Amyloid precursor protein Animals Humans Donepezil Binding site Uracil Binding Sites biology Chemistry Active site Ligand (biochemistry) Acetylcholinesterase Treatment Outcome 030104 developmental biology biology.protein Cholinesterase Inhibitors 030217 neurology & neurosurgery Acetylcholine medicine.drug |
| Zdroj: | Neuropharmacology. 155:131-141 |
| ISSN: | 0028-3908 |
| Popis: | Profound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer's disease. This study was set up to analyze possible neuroprotective effects of two dual binding site inhibitors of acetylcholinesterase (AChE), a new 6-methyluracil derivative, C-35, and the clinically used inhibitor donepezil. Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge. Molecular dynamics simulations indicated that the external flexible part of the ligand establishes multiple transient interactions with the enzyme peripheral anionic site. Thus, C-35 is a dual binding site inhibitor of AChE. In transgenic mice, expressing a chimeric mouse/human amyloid precursor protein and a human presenilin-1 mutant, C-35 (5 mg/kg, i.p) and donepezil (0.75 mg/kg, i.p) partially reversed synapse loss, decreased the number of amyloid plaques, and restored learning and memory. To separate temporal symptomatic therapeutic effects, associated with the increased lifetime of acetylcholine in the brain, from possible disease-modifying effect, an experimental protocol based on drug withdrawal from therapy was performed. When administration of C-35 and donepezil was terminated three weeks after the trial started, animals that were receiving C-35 showed a much better ability to learn than those who received vehicle or donepezil. Our results provide additional evidence that dual binding site inhibitors of AChE have Alzheimer's disease-modifying action. |
| Databáze: | OpenAIRE |
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