Uncompetitive antagonism of AMPA receptors: Mechanistic insights from studies of polyamine toxin derivatives

Research output: Contribution to journalJournal articleResearchpeer-review

Trine F Andersen, Denis B Tikhonov, Ulrik Bølcho, Konstantin Bolshakov, Jared K Nelson, Florentina Pluteanu, Ian R Mellor, Jan Egebjerg, Kristian Strømgaard

Philanthotoxins are uncompetitive antagonists of Ca2+-permeable AMPA receptors presumed to bind to the pore-forming region, but a detailed molecular mechanism for this interaction is missing. Here a small library of novel philanthotoxins was designed and synthesized using a solid-phase strategy. The biological activities were investigated at cloned and "native" AMPA receptors using electrophysiological techniques. A distinct relationship between length of the polyamine moiety and the location of a secondary amino group was observed. Fitting the data to the Woodhull equation allowed the first experimental demonstration of the relative location and orientation of the philanthotoxin molecule in the receptor. These results were corroborated by in silico studies using a homology model of the AMPA receptor ion channel. Together these studies provide strong evidence for a molecular mechanism by which polyamine toxins antagonize the AMPA receptor ion channel and provide the basis for rational development of uncompetitive antagonists of AMPA receptors.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume49
Issue number18
Pages (from-to)5414-5423
Number of pages10
ISSN0022-2623
DOIs
Publication statusPublished - 7 Sep 2006

    Research areas

  • Animals, Bacterial Proteins, Binding Sites, Calcium, Models, Molecular, Molecular Structure, Oocytes, Patch-Clamp Techniques, Polyamines, Potassium Channels, Rats, Receptors, AMPA, Stereoisomerism, Structure-Activity Relationship, Toxins, Biological, Tyrosine, Wasp Venoms, Xenopus laevis

ID: 45823493