The synthesis and pharmacological characterization of a novel series of 4-aryl-substituted kainic acid analogs are described. Receptor affinities were determined on recombinantly expressed humGluR6 kainate receptors and on [3H]kainate binding to rat forebrain kainate receptors. Functional agonist potencies were assessed using whole cell voltage clamp 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. Substitution on phenyl led to a series of compounds with varying affinity for this kainate receptor. Agonist potency correlated with receptor affinity and with no derivative could antagonist activity be identified. Affinities for the humGluR6 kainate receptor were approximately 10-50 less than the observed affinities at rat forebrain kainate receptors. Furthermore, within the series of 4-aryl-substituted kainic acid analogs, there was a high degree of correlation between binding affinities for humGluR6 receptors and competition with kainate binding to rat forebrain kainate receptors.