title: Acetylcholinesterase inhibitors from the toadstool Cortinarius infractus.
abstract: 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 pi-pi-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 Abeta-peptides but not on AChE induced Abeta-peptide aggregation. Low cytotoxicity as well as calculated pharmacokinetic data suggest that the natural products could be useful candidates for further drug development.
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Geissler
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brandt
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Porzel
authors.affiliation: Probiodrug AG, Weinbergweg 22, D-06120 Halle (Saale), Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Schlenzig
authors.affiliation: Probiodrug AG, Weinbergweg 22, D-06120 Halle (Saale), Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kehlen
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Wessjohann
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Arnold
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000363:Agaricales / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology; D048690:Fruiting Bodies, Fungal / Q000737:chemistry*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C549691:10-hydroxy-infractopicrin; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; C549692:infractopicrin; D000110:Acetylcholinesterase