SYNTHESIS OF A SERIES OF ARYL KAINIC ACID ANALOGS AND EVALUATION IN CELLS STABLY EXPRESSING THE KAINATE RECEPTOR HUMGLUR6

The synthesis and pharmacological characterization of a novel series o f 4-aryl-substituted kainic acid analogs are described. Receptor affin ities were determined on recombinantly expressed humGluR6 kainate rece ptors and on [H-3]kainate binding to rat forebrain kainate receptors. Functional agonist potencies were assessed using whole cell voltage cl amp recordings in cells expressing humGluR6 receptors. Substitution of phenyl for the methyl at the C-4 position of kainic acid produced 11 which has high affinity and agonist potency at the GluR6 receptor. Sub stitution on phenyl led to a series of compounds with varying affinity for this kainate receptor. Agonist potency correlated with receptor a ffinity and with no derivative could antagonist activity be identified . Affinities for the humGluR6 kainate receptor were approximately 10-5 0 less than the observed affinities at rat forebrain kainate receptors . Furthermore, within the series of 4-aryl-substituted kainic acid ana logs, there was a high degree of correlation between binding affinitie s for humGluR6 receptors and competition with kainate binding to rat f orebrain kainate receptors.