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Geißler, T.; Brandt, W.; Porzel, A.; Schlenzig, D.; Kehlen, A.; Wessjohann, L.; Arnold, N. Acetylcholinesterase inhibitors from the toadstool Cortinarius infractus Bioorg Med Chem 18, 2173-2177, (2010) DOI: 10.1016/j.bmc.2010.01.074
Inhibition of acetylcholinesterase (AChE) and therefore prevention of acetylcholine degradation is one of the most accepted therapy opportunities for Alzheimer´s disease (AD), today. Due to lack of selectivity of AChE inhibitor drugs on the market, AD-patients suffer from side effects like nausea or vomiting. In the present study the isolation of two alkaloids, infractopicrin (1) and 10-hydroxy-infractopicrin (2), from Cortinarius infractus Berk. (Cortinariaceae) is presented. Both compounds show AChE-inhibiting activity and possess a higher selectivity than galanthamine. Docking studies show that lacking π–π-interactions in butyrylcholinesterase (BChE) are responsible for selectivity. Studies on other AD pathology related targets show an inhibitory effect of both compounds on self-aggregation of Aβ-peptides but not on AChE induced Aβ-peptide aggregation. Low cytotoxicity as well as calculated pharmacokinetic data suggest that the natural products could be useful candidates for further drug development.
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