Structure-activity relationship studies of argiotoxins: selective and potent inhibitors of ionotropic glutamate receptors

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Mette H Poulsen, Simon Lucas, Tinna B Bach, Anne F Barslund, Claudius Wenzler, Christel B Jensen, Anders S Kristensen, Kristian Strømgaard

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.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume56
Issue number3
Pages (from-to)1171-1181
Number of pages11
DOIs
Publication statusPublished - 14 Feb 2013

    Research areas

  • Chromatography, High Pressure Liquid, Indoleacetic Acids, Magnetic Resonance Spectroscopy, Mass Spectrometry, Polyamines, Receptors, Ionotropic Glutamate, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship

ID: 45795534