title: Design, synthesis, and pharmacological characterization of polyamine toxin derivatives: potent ligands for the pore-forming region of AMPA receptors.
abstract: Polyamine toxins, such as philanthotoxins, are low-molecular-weight compounds isolated from spiders and wasps, which modulate ligand-gated ion channels in the nervous system. Philanthotoxins bind to the pore-forming region of AMPA receptors, a subtype of glutamate receptors which are important for memory formation and are involved in neurodegenerative diseases. Previous studies have demonstrated that modification of the polyamine moiety of philanthotoxins can lead to very potent and highly selective ligands for the AMPA receptor, as exemplified with philanthotoxin-56. Much less attention has been paid to the importance of the aromatic head group of philanthotoxins, but herein we demonstrate that modification of this moiety leads to a significant improvement in potency relative to philanthotoxin-56 at cloned AMPA receptors. Interestingly, the incorporation of an adamantane moiety is particularly favorable, and the most potent compound has a Ki value of 2 nM, making it the most potent uncompetitive antagonist of AMPA receptors described to date. Such compounds are potentially useful as neuroprotective agents.
authors.affiliation: Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Lars S
authors.initials: LS
authors.lastname: Jensen
authors.forename: Ulrik
authors.initials: U
authors.lastname: Bølcho
authors.forename: Jan
authors.initials: J
authors.lastname: Egebjerg
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000187:drug effects*; D014981:Xenopus
chemical_list: D008024:Ligands; D011073:Polyamines; D018091:Receptors, AMPA