title: The effects of conformational constraints in the polyamine moiety of philanthotoxins on AMPAR inhibition.
abstract: Philanthotoxin-433 (PhTX-433) is a known potent inhibitor of ionotropic glutamate receptors, and analogues have been synthesised to identify more potent and selective antagonists. Herein we report the synthesis of four PhTXs with a cyclopropane moiety introduced into their polyamine chain, and their inhibition of an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subtype by using two-electrode voltage-clamp assays on Xenopus oocytes expressing the GluA1flop subunit. All analogues were found to be more potent than PhTX-343, with trans-cyclopropyl-PhTX-343 being the most potent (∼28-fold) and cis-cyclopropyl-PhTX-343 least potent (∼4-fold). Both cis- and trans-cyclopropyl-PhTX-444 had intermediate potency (both∼12-fold). Molecular modelling indicates that a cyclopropane moiety confers a favourable steric constraint to the polyamine part, but this is compromised by a cis conformation due to enhanced intramolecular folding. Elongated PhTX-444 analogues alleviate this to some extent, but optimal positioning of the amines is not permitted.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark).
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
authors.forename: John W
authors.initials: JW
authors.lastname: Grzeskowiak
authors.forename: Denis B
authors.initials: DB
authors.lastname: Tikhonov
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Jaroszewski
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mellor
mesh_terms: D000818:Animals; D006860:Hydrogen Bonding; D007536:Isomerism; D008958:Models, Molecular; D008968:Molecular Conformation; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology; D011073:Polyamines / Q000737:chemistry* / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014981:Xenopus / Q000254:growth & development
chemical_list: D010636:Phenols; D011073:Polyamines; D018091:Receptors, AMPA; C074003:philanthotoxin 343
keywords: glutamate receptors; ion channels; natural products; polyamine toxins; solid-phase synthesis