title: Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine.
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 approximately 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 GluK1 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.
authors: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors: L Leanne
authors: LL
authors: Lash-Van Wyhe
authors: Pekka A
authors: PA
authors: Postila
authors: Koichi
authors: K
authors: Tsubone
authors: Makoto
authors: M
authors: Sasaki
authors: Olli T
authors: OT
authors: Pentikäinen
authors: Ryuichi
authors: R
authors: Sakai
authors: Geoffrey T
authors: GT
authors: Swanson
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007608:Kainic Acid / Q000493:pharmacokinetics; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed / Q000379:methods; D018408:Patch-Clamp Techniques / Q000379:methods; D021122:Protein Subunits / Q000235:genetics; D011869:Radioligand Assay / Q000379:methods; D018092:Kainic Acid Receptors / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000493:pharmacokinetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000493:pharmacokinetics
chemical_list: D000409:Alanine; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D049452:Green Fluorescent Proteins; D007608:Kainic Acid; D008024:Ligands; D021122:Protein Subunits; D018092:Kainic Acid Receptors; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C121741:dysiherbaine; C485184:enhanced green fluorescent protein; C438974:neodysiherbaine A