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Search for multifunctional agents against Alzheimer's disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives
J. Jończyk, K. Lodarski, M. Staszewski, J. Godyń, P. Zaręba, O. Soukup, J. Janockova, J. Korabecny, K. Sałat, N. Malikowska-Racia, M. Hebda, N. Szałaj, B. Filipek, K. Walczyński, B. Malawska, M. Bajda,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu hodnotící studie, časopisecké články, práce podpořená grantem
- MeSH
- acetylcholinesterasa chemie MeSH
- adjuvancia anestetická toxicita MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- amnézie chemicky indukované farmakoterapie MeSH
- butyrylcholinesterasa chemie MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- ligandy MeSH
- modely nemocí na zvířatech * MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- myši MeSH
- piperaziny chemie MeSH
- receptory histaminu H3 chemie metabolismus MeSH
- skopolamin toxicita MeSH
- techniky in vitro MeSH
- výpočetní biologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood-brain barrier penetration in test conditions. The most promising compound, A12, chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA2 = 8.27), inhibitory activity against both AChE (IC50 = 13.96 μM), and BuChE (IC50 = 14.62 μM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice.
Citace poskytuje Crossref.org
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- $a Jończyk, Jakub $u Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
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