Novel Analogs and Stereoisomers of the Marine Toxin Neodysiherbaine with Specificity for Kainate Receptors

• DOI: 10.1124/jpet.107.129890
• Publication Date: 2007-11-22T02:05:30Z
• Authors: L. Leanne Lash; James M. Sanders; Nobuyuki Akiyama; Muneo Shoji; Pekka Postila; Olli T. Pentikäinen; Makoto Sasaki; Ryuichi Sakai; Geoffrey T. Swanson
• Keywords: Kainate receptor; Convulsants

Antagonists for kainate receptors (KARs), a family of glutamategated ion channels, are efficacious in number animal models neuropathologies, including epilepsy, migraine pain, and anxiety. To produce molecules with novel selectivities receptors, we generated three sets analogs related to the natural marine convulsant neodysiherbaine (neoDH), characterized their pharmacological profiles. Radioligand displacement assays recombinant α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) KARs demonstrated that functional groups at two positions on neoDH molecule critical determinants; only binding glutamate receptor (GluR)5-2a subunit was relatively insensitive structural modifications groups. NeoDH which l-glutamate congener disrupted by epimerization retained low affinity GluR5-2a GluR6a KAR subunits. Most showed agonist activity electrophysiological recordings from human embryonic kidney-T/17 cells expressing KARs, similar neoDH. In contrast, 2,4-epi-neoDH inhibited currents evoked both receptor-expressing cells. Therefore, this compound represents first exhibit antagonist subunits without concurrent AMPA Finally, synthetic ligands closely correlated seizurogenic potency, strongly supporting role containing reaction agonists. The described here offer further insight into determinants ligand selectivity potentially represent useful tools studying synaptic physiology pathology.