Pharmacological activity of synthetic analogs of dysiherbaine on glutamate receptors

• Published in: The FASEB journal 2006-03, Vol.20 (4), p.A687-A687
• Main Authors: Lash, Laura Leanne, Sanders, James M, Shoji, Muneo, Sasaki, Makoto, Sakai, Ryuichi, Swanson, Geoffrey T
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.20.4.A687-d

The marine toxin dysiherbaine (DH) and its natural analog, neodysiherbaine (NDH), are potent and subunit‐selective kainate receptor (KAR) agonists. The substituents at the C8 and C9 positions are critical determinants of pharmacological activity. Here we characterized the pharmacological specificity of stereoisomers and deoxy analogs of NDH on non‐NMDA glutamate receptors. Radioligand displacement assays were performed with GluR1 and GluR2 AMPA receptor subunits and GluR5, GluR6, and KA2 KAR subunits. 8‐epiNDH, 8‐deoxyNDH and 9‐deoxyNDH retained high affinity only for GluR5 KAR subunits, whereas 8,9‐epiNDH had markedly reduced affinity for all AMPA and KA receptors tested. Interestingly, 4‐epiNDH displaced 3H‐KA from both GluR5 and GluR6 subunits with Ki values of 2.4 and 7.7 μM but had no detectable affinity for AMPA receptors; furthermore, 4‐epiNDH demonstrated antagonist activity in patch clamp recordings from transfected HEK‐293 cells. Similarly, 10 μM 8‐epiNDH completely inhibited GluR5 glutamate‐evoked currents from GluR5 receptors but only modestly inhibited GluR6 receptors. Our data supports the importance of the C8 and C9 substituents in conferring activity on KARs and suggests that manipulation of the functional groups could produce novel pharmacological profiles. KAR selective compounds will contribute to understanding the role of these receptors in the central nervous system. Supported by NIDA (LLL) and NINDS (GTS)