Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine

NEUROPHARMACOLOGY

卷:58

Article

Lash-Van Wyhe, L. Leanne^1,2  Postila, Pekka A.^3,4  Tsubone, Koichi⁵  Sasaki, Makoto⁵  Pentikainen, Olli T.^3,4  Sakai, Ryuichi⁶  Swanson, Geoffrey T.¹ 

[1] Northwestern Univ, Feinberg Sch Med, Dept Biol Chem & Mol Pharmacol, Chicago, IL 60611 USA

[2] Univ Texas Med Branch, Dept Pharmacol & Toxicol, Galveston, TX USA

[3] Univ Jyvaskyla, Nanosci Ctr, FI-40014 Jyvaskyla, Finland

[4] Univ Jyvaskyla, Dept Biol & Environm Sci, FI-40014 Jyvaskyla, Finland

[5] Tohoku Univ, Lab Biostruct Chem, Grad Sch Life Sci, Aoba Ku, Sendai, Miyagi 980, Japan

[6] Hokkaido Univ, Fac Fisheries Sci, Hakodate, Hokkaido 0418611, Japan

关键词: Glutamate receptor;    Marine natural product;    Synthetic;    Radioligand binding;    Electrophysiology;    Ligand-binding domain;   

DOI  :  10.1016/j.neuropharm.2009.11.013

来源: Elsevier

【 摘 要 】

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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