title: Uncompetitive antagonism of AMPA receptors: Mechanistic insights from studies of polyamine toxin derivatives.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark.
authors.forename: Trine F
authors.initials: TF
authors.lastname: Andersen
authors.forename: Denis B
authors.initials: DB
authors.lastname: Tikhonov
authors.forename: Ulrik
authors.initials: U
authors.lastname: Bølcho
authors.forename: Konstantin
authors.initials: K
authors.lastname: Bolshakov
authors.forename: Jared K
authors.initials: JK
authors.lastname: Nelson
authors.forename: Florentina
authors.initials: F
authors.lastname: Pluteanu
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mellor
authors.forename: Jan
authors.initials: J
authors.lastname: Egebjerg
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D002118:Calcium / Q000502:physiology; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000737:chemistry; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014118:Toxins, Biological / Q000737:chemistry*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry; D014862:Wasp Venoms / Q000737:chemistry; D014982:Xenopus laevis
chemical_list: D001426:Bacterial Proteins; D011073:Polyamines; D015221:Potassium Channels; D018091:Receptors, AMPA; D014118:Toxins, Biological; D014862:Wasp Venoms; C505667:philanthotoxin-56; D014443:Tyrosine; C034092:delta-philanthotoxin; D002118:Calcium