Acetylcholinesterase inhibitory activity of scopolin and scopoletin discovered by virtual screening of natural products.
For the targeting selection of acetylcholinesterase (AChE) inhibitors from natural sources we generated a structure-based pharmacophore model utilizing an in silico filtering experiment for the discovery of promising candidates out of a 3D multiconformational database consisting of more than 110,000 natural products. In our study, scopoletin (1) and its glucoside scopolin (2) emerged as potential AChE inhibitors by the virtual screening procedure. They were isolated by different chromatographic methods from the medicinal plant Scopolia carniolica Jaqc. and tested in an enzyme assay using Ellman's reagent. They showed moderate, but significant, dose-dependent and long-lasting inhibitory activities. In the in vivo experiments (icv application of 2 micromol) 1 and 2 increased the extracellular acetylcholine (ACh) concentration in rat brain to about 170% and 300% compared to basal release, respectively. At the same concentration, the positive control galanthamine increased the ACh concentration to about the same level as 1. These are the first in vivo results indicating an effect of coumarins on brain ACh.
Rollinger
Judith M
JM
Department of Pharmacognosy, Leopold-Franzens University of Innsbruck, A-6020 Innsbruck, Austria. judith.rollinger@uibk.ac.at
Hornick
Ariane
A
Langer
Thierry
T
Stuppner
Hermann
H
Prast
Helmut
H
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D003374:Coumarins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005960:Glucosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008958:Models, Molecular; D015394:Molecular Structure; D010936:Plant Extracts / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012603:Scopoletin / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D032603:Scopolia
D002800:Cholinesterase Inhibitors; D003374:Coumarins; D005960:Glucosides; D010936:Plant Extracts; C417572:scopolin; D000110:Acetylcholinesterase; D012603:Scopoletin; D000109:Acetylcholine