Acetylcholinesterase inhibitors from the toadstool Cortinarius infractus.
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.
Geissler
Torsten
T
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
Brandt
Wolfgang
W
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
Porzel
Andrea
A
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
Schlenzig
Dagmar
D
Probiodrug AG, Weinbergweg 22, D-06120 Halle (Saale), Germany.
Kehlen
Astrid
A
Probiodrug AG, Weinbergweg 22, D-06120 Halle (Saale), Germany.
Wessjohann
Ludger
L
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
Arnold
Norbert
N
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
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
C549691:10-hydroxy-infractopicrin; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; C549692:infractopicrin; D000110:Acetylcholinesterase