Acetylcholinesterase Inhibitory Activity of Scopolin and Scopoletin Discovered by Virtual Screening of Natural Products

• Published in: Journal of medicinal chemistry 2004-12, Vol.47 (25), p.6248-6254
• Main Authors: Rollinger, Judith M, Hornick, Ariane, Langer, Thierry, Stuppner, Hermann, Prast, Helmut
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Acetylcholinesterase - chemistry; Animals; Biological and medical sciences; Brain - metabolism; Cholinergic system; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Coumarins - chemistry; Coumarins - isolation & purification; Coumarins - pharmacology; Glucosides - chemistry; Glucosides - isolation & purification; Glucosides - pharmacology; Injections, Intraventricular; Medical sciences; Models, Molecular; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Plant Extracts - chemistry; Quantitative Structure-Activity Relationship; Rats; Scopoletin - chemistry; Scopoletin - isolation & purification; Scopoletin - pharmacology; Scopolia
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049655r

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 μmol) 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.