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Title

In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier

AuthorsChlebek, Jakub; Korábečný, Jan; Doležal, Rafael; Štěpánková, Šárka; Pérez, Daniel I. ; Hošťálková, Anna; Opletal, Lubomír; Cahlíková, Lucie; Macáková, Kateřina; Kučera, Tomáš; Hrabinová, Martina; Jun, Daniel
Keywords(+)-thalictricavine
(+)-canadine
Cholinesterases
Kinetic study
Molecular docking
Blood–brain barrier permeability
Issue Date5-Apr-2019
PublisherMultidisciplinary Digital Publishing Institute
CitationMolecules 24(7): 1340 (2019)
AbstractIn recent studies, several alkaloids acting as cholinesterase inhibitors were isolated from <i>Corydalis cava</i> (Papaveraceae). Inhibitory activities of (+)-thalictricavine (<b>1</b>) and (+)-canadine (<b>2</b>) on human acetylcholinesterase (<i>h</i>AChE) and butyrylcholinesterase (<i>h</i>BChE) were evaluated with the Ellman’s spectrophotometric method. Molecular modeling was used to inspect the binding mode of compounds into the active site pocket of <i>h</i>AChE. The possible permeability of <b>1</b> and <b>2</b> through the blood–brain barrier (BBB) was predicted by the parallel artificial permeation assay (PAMPA) and logBB calculation. In vitro, <b>1</b> and <b>2</b> were found to be selective <i>h</i>AChE inhibitors with IC<sub>50</sub> values of 0.38 ± 0.05 µM and 0.70 ± 0.07 µM, respectively, but against <i>h</i>BChE were considered inactive (IC<sub>50</sub> values > 100 µM). Furthermore, both alkaloids demonstrated a competitive-type pattern of <i>h</i>AChE inhibition and bind, most probably, in the same AChE sub-site as its substrate. In silico docking experiments allowed us to confirm their binding poses into the active center of <i>h</i>AChE. Based on the PAMPA and logBB calculation, <b>2</b> is potentially centrally active, but for <b>1</b> BBB crossing is limited. In conclusion, <b>1</b> and <b>2</b> appear as potential lead compounds for the treatment of Alzheimer’s disease.
Publisher version (URL)http://dx.doi.org/10.3390/molecules24071340
URIhttp://hdl.handle.net/10261/180183
DOI10.3390/molecules24071340
E-ISSN1420-3049
Appears in Collections:(CIB) Artículos
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