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Tytuł:: The ATP-regulated Ki^+ channel in mitochondria: five years after its discovery
Autorzy:: Szewczyk, Adam
Wydawca:: Polskie Towarzystwo Biochemiczne
Powiązania:: https://bibliotekanauki.pl/articles/1045097.pdf Link otwiera się w nowym oknie
Dostawca treści:: Biblioteka Nauki

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Tytuł:: Early Drug Discovery Prediction of Proarrhythmia Potential and Its Covariates
Autorzy:: Polak, Sebastian
Pugsley, Michael K.
Garnett, Christine
Stockbridge, Norman
Wiśniowska, Barbara
Dostawca treści:: Repozytorium Uniwersytetu Jagiellońskiego

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Tytuł:: Discovery of novel multifunctional ligands targeting GABA transporters, butyrylcholinesterase, β-secretase, and amyloid β aggregation as potential treatment of Alzheimers disease
Autorzy:: Hofner, Georg C.
Espargaró, Alba
Maj, Maciej
Jóźwiak, Krzysztof
Sałat, Kinga
Bajda, Marek
Malawska, Barbara
Pasieka, Anna
Latacz, Gniewomir
Kulig, Katarzyna
Łątka, Kamil
Wanner, Klaus T.
Gryzło, Beata
Skrzypczak-Wiercioch, Anna
Godyń, Justyna
Sabate, Raimon
Zaręba, Paula
Panek, Dawid
Mazur, Gabriela
Opis:: Alzheimer's disease (AD) is a global health problem in the medical sector that will increase over time. The limited treatment of AD leads to the search for a new clinical candidate. Considering the multifactorial nature of AD, a strategy targeting number of regulatory proteins involved in the development of the disease is an effective approach. Here, we present a discovery of new multi-target-directed ligands (MTDLs), purposely designed as GABA transporter (GAT) inhibitors, that successfully provide the inhibitory activity against butyrylcholinesterase (BuChE), β-secretase (BACE1), amyloid β aggregation and calcium channel blockade activity. The selected GAT inhibitors, 19c and 22a – N-benzylamide derivatives of 4-aminobutyric acid, displayed the most prominent multifunctional profile. Compound 19c (mGAT1 IC50 = 10 μM, mGAT4 IC$_{50}$ = 12 μM and BuChE IC$_{50}$ = 559 nM) possessed the highest hBACE1 and Aβ40 aggregation inhibitory activity (IC$_{50}$ = 1.57 μM and 99 % at 10 μM, respectively). Additionally, it showed a decrease in both the elongation and nucleation constants of the amyloid aggregation process. In contrast compound 22a represented the highest activity and a mixed-type of eqBuChE inhibition (IC$_{50}$ = 173 nM) with hBACE1 (IC$_{50}$ = 9.42 μM), Aβ aggregation (79 % at 10 μM) and mGATs (mGAT1 IC$_{50}$ = 30 μM, mGAT4 IC$_{50}$ = 25 μM) inhibitory activity. Performed molecular docking studies described the mode of interactions with GATs and enzymatic targets. In ADMET in vitro studies both compounds showed acceptable metabolic stability and low neurotoxicity. Successfully, compounds 19c and 22a at the dose of 30 mg/kg possessed statistically significant antiamnesic properties in a mouse model of amnesia caused by scopolamine and assessed in the novel object recognition (NOR) task or the passive avoidance (PA) task.
Dostawca treści:: Repozytorium Uniwersytetu Jagiellońskiego

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