LY339434, a GluR5 kainate receptor agonist

Abstract

The activity of a γ-substituted glutamate analogue, (2 S, 4 R, 6E)-2-amino-4-carboxy-7-(2-naphthyl)hept-6-enoic acid (LY339434) and (2 S,4 R)-4-methylglutamic acid at ionotropic glutamate receptors has been examined. Ligand binding studies were performed using [ 3H] AMPA binding to membranes expressing either homomeric recombinant GluR1, GluR2, GluR4 receptors, and [ 3H] kainate binding to GluR5 and GluR6 kainate receptors. LY339434 and (2 S,4 R)-4-methylglutamic acid showed selectivity in ligand binding studies for kainate receptors over AMPA receptors. Within the kainate class of glutamate receptors, LY339434 showed selectivity for GluR5 over GluR6 whereas (2 S,4 R)-4-methylglutamic acid showed high affinity for both GluR5 and GluR6 kainate receptors. Examination of the functional activity of LY339434 and (2 S,4 R)-4-methylglutamic acid showed that both compounds evoked inward currents in dorsal root ganglion neurons (DRG) with estimated EC 50 values of 0.8±0.2 μM and 0.17±0.04 μM, respectively. In GluR5 expressing HEK 293 cells, LY339434 evoked inward currents with an estimated EC 50 value of 2.5±0.9 μM but had little effect on GluR6 expressing cells at concentrations less than 100 μM. LY339434 was a weak AMPA receptor agonist ( EC 50 values>300 μM) as determined by activity in acutely isolated cerebellar Purkinje neurons. LY339434 and (2 S,4 R)-4-methylglutamic acid had agonist activity at NMDA receptors studied in cultured hippocampal neurons with EC 50s of 2.5 μM and 11.7 μM, respectively. These results indicate that both LY339434 and (2 S,4 R)-4-methyl glutamic acid may be useful pharmacological tools for the examination of kainate receptors.