A1 Refereed original research article in a scientific journal
Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine
Authors: Lash-Van Wyhe LL, Postila PA, Tsubone K, Sasaki M, Pentikainen OT, Sakai R, Swanson GT
Publisher: PERGAMON-ELSEVIER SCIENCE LTD
Publication year: 2010
Journal: Neuropharmacology
Journal name in source: NEUROPHARMACOLOGY
Journal acronym: NEUROPHARMACOLOGY
Volume: 58
Issue: 3
First page : 640
Last page: 649
Number of pages: 10
ISSN: 0028-3908
DOI: https://doi.org/10.1016/j.neuropharm.2009.11.013
Abstract
Kainate receptor antagonists have potential as therapeutic agents in a number of neuropathologies. Synthetic modification of the convulsant marine toxin neodysiherbaine A (NDH) previously yielded molecules with a diverse set of pharmacological actions on kainate receptors. Here we characterize three new synthetic analogs of NDH that contain substituents at the C10 position in the pyran ring of the marine toxin. The analogs exhibited high-affinity binding to the GluK1 (GluR5) subunit and lower affinity binding to GluK2 (GluR6) and GluK3 (GluR7) subunits in radioligand displacement assays with recombinant kainate and AMPA receptors. As well, the natural toxin NDH exhibited similar to 100-fold selectivity for GluK2 over GluK3 subunits, which was attributable to the C8 hydroxyl group in NDH. We used molecular dynamic simulations to determine the specific interactions between NDH and residues within the ligand-binding domains of these two kainate receptor subunits that contribute to the divergent apparent affinities for the compound. These data demonstrate that interactions with the GluKI subunit are preserved in analogs with substitutions at C10 in NDH and further reveal the determinants of selectivity and pharmacological activity of molecules acting on kainate receptor subunits. which could aid in design of additional compounds that target these receptors. (C) 2009 Elsevier Ltd. All rights reserved.
Kainate receptor antagonists have potential as therapeutic agents in a number of neuropathologies. Synthetic modification of the convulsant marine toxin neodysiherbaine A (NDH) previously yielded molecules with a diverse set of pharmacological actions on kainate receptors. Here we characterize three new synthetic analogs of NDH that contain substituents at the C10 position in the pyran ring of the marine toxin. The analogs exhibited high-affinity binding to the GluK1 (GluR5) subunit and lower affinity binding to GluK2 (GluR6) and GluK3 (GluR7) subunits in radioligand displacement assays with recombinant kainate and AMPA receptors. As well, the natural toxin NDH exhibited similar to 100-fold selectivity for GluK2 over GluK3 subunits, which was attributable to the C8 hydroxyl group in NDH. We used molecular dynamic simulations to determine the specific interactions between NDH and residues within the ligand-binding domains of these two kainate receptor subunits that contribute to the divergent apparent affinities for the compound. These data demonstrate that interactions with the GluKI subunit are preserved in analogs with substitutions at C10 in NDH and further reveal the determinants of selectivity and pharmacological activity of molecules acting on kainate receptor subunits. which could aid in design of additional compounds that target these receptors. (C) 2009 Elsevier Ltd. All rights reserved.
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