Polyamine amides are potent antagonists of many classes of ionotropic receptor. Here, calculations of the conformations of 26 polyamine amides using molecular mechanics methodology have shown that intramolecular hydrogen bonds strongly influence the in vacuo three-dimensional structure of a polyamine amide. Although these bonds are less stable in an aqueous environment, they may occur more when a polyamine amide interacts with a binding site. The estimated three-dimensional structures of polyamine amides provide an explanation for the differences in their antagonist potency at quisqualate-sensitive ionotropic glutamate receptors (qGluR) observed in experimental studies. Relative antagonist potency at qGluR is correlated with the number of free amino groups on a polyamine amide, i.e. those not involved in intramolecular hydrogen bonds. Also, intramolecular hydrogen bonds significantly restrict the conformational freedom of the uncharged moiety of a polyamine amide. Docking of polyamine amides to a molecular model of a mammalian AMPA receptor (GluR1) channel shows that intramolecular H-bonds may also provide a good structural explanation for the action of these compounds at this site.