Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine.
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.
Lash-Van Wyhe
L Leanne
LL
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Postila
Pekka A
PA
Tsubone
Koichi
K
Sasaki
Makoto
M
Pentikäinen
Olli T
OT
Sakai
Ryuichi
R
Swanson
Geoffrey T
GT
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
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