The effects of conformational constraints in the polyamine moiety of philanthotoxins on AMPAR inhibition

ChemMedChem. 2014 Aug;9(8):1725-31. doi: 10.1002/cmdc.201402109. Epub 2014 Jul 8.


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.

Keywords: glutamate receptors; ion channels; natural products; polyamine toxins; solid-phase synthesis.

MeSH terms

  • Animals
  • Hydrogen Bonding
  • Isomerism
  • Models, Molecular*
  • Molecular Conformation
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • Phenols / chemistry*
  • Phenols / pharmacology
  • Polyamines / chemistry*
  • Polyamines / pharmacology
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / metabolism
  • Structure-Activity Relationship
  • Xenopus / growth & development


  • Phenols
  • Polyamines
  • Receptors, AMPA
  • philanthotoxin 343