title: Structure-activity relationship studies of argiotoxins: selective and potent inhibitors of ionotropic glutamate receptors.
abstract: Argiotoxin-636 (ArgTX-636), a natural product from the spider Argiope lobata, is a potent but nonselective open-channel blocker of ionotropic glutamate (iGlu) receptors. Here, three series of analogues were designed to exploit selectivity among iGlu receptors, taking advantage of a recently developed solid-phase synthetic methodology for the synthesis of ArgTX-636 and analogues. Initially, the importance of secondary amino groups in the polyamine chain was studied by the synthesis of systematically modified ArgTX-636 analogues, which were evaluated for pharmacological activity at NMDA and AMPA receptors. This led to the identification of two compounds with preference for NMDA and AMPA receptors, respectively. These were further elaborated by systematically changing the aromatic headgroup and linker amino acid leading to compounds with increased potency and selectivity for NMDA and AMPA receptors, respectively. Thus, the first structure-activity relationship study of ArgTX-636 has been carried out and has provided lead compounds for probing the ion channel region of iGlu receptors.
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors: Mette H
authors: MH
authors: Poulsen
authors: Simon
authors: S
authors: Lucas
authors: Tinna B
authors: TB
authors: Bach
authors: Anne F
authors: AF
authors: Barslund
authors: Claudius
authors: C
authors: Wenzler
authors: Christel B
authors: CB
authors: Jensen
authors: Anders S
authors: AS
authors: Kristensen
authors: Kristian
authors: K
authors: Strømgaard
mesh_terms: D002851:Chromatography, High Pressure Liquid; D007210:Indoleacetic Acids / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011073:Polyamines / Q000494:pharmacology*; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D007210:Indoleacetic Acids; D011073:Polyamines; D058468:Receptors, Ionotropic Glutamate; C558368:argiotoxin-636