title: General synthesis of β-alanine-containing spider polyamine toxins and discovery of nephila polyamine toxins 1 and 8 as highly potent inhibitors of ionotropic glutamate receptors.
abstract: Certain spiders contain large pools of polyamine toxins, which are putative pharmacological tools awaiting further discovery. Here we present a general synthesis strategy for this class of toxins and prepare five structurally varied polyamine toxins. Electrophysiological testing at three ionotropic glutamate receptor subtypes reveals that two of these, Nephila polyamine toxins 1 (NPTX-1) and 8 (NPTX-8), comprise intriguing pharmacological activities by having subnanomolar IC(50) values at kainate receptors.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Lucas
authors.forename: Mette H
authors.initials: MH
authors.lastname: Poulsen
authors.forename: Niels G
authors.initials: NG
authors.lastname: Nørager
authors.forename: Anne F
authors.initials: AF
authors.lastname: Barslund
authors.forename: Tinna B
authors.initials: TB
authors.lastname: Bach
authors.forename: Anders S
authors.initials: AS
authors.lastname: Kristensen
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: D000818:Animals; D001216:Asparagine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007210:Indoleacetic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D011073:Polyamines / Q000138:chemical synthesis* / Q000494:pharmacology; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D013111:Spider Venoms / Q000737:chemistry*; D013112:Spiders / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014118:Toxins, Biological / Q000138:chemical synthesis* / Q000494:pharmacology; D015091:beta-Alanine / Q000737:chemistry*
chemical_list: D001216:Asparagine; D007210:Indoleacetic Acids; D011073:Polyamines; D058468:Receptors, Ionotropic Glutamate; D018092:Kainic Acid Receptors; D013111:Spider Venoms; D014118:Toxins, Biological; D015091:beta-Alanine; C577966:2-(2-(1H-indol-3-yl)acetamido)-N1-(5-(3-(4-(3-aminopropylamino)butylamino)propanamido)pentyl)succinamide; C577965:N1-(5-(3-(4-(3-aminopropylamino)butylamino)propanamido)pentyl)-2-(2-(4-hydroxy-1H-indol-3-yl)acetamido)succinamide