LY339434, A GLUR5 KAINATE RECEPTOR AGONIST

The activity of a gamma-substituted glutamate analogue, (2S, 4R, 6E)-2 -amino-4-carboxy-7-(2-naphthyl)hept-6-enoic acid (LY339434) and (2S,4R )-4-methylglutamic acid at ionotropic glutamate receptors has been exa mined. Ligand binding studies were performed using [H-3] AMPA binding to membranes expressing either homomeric recombinant GluR1, GluR2, Glu R4 receptors, and [H-3] kainate binding to GluR5 and GluR6 kainate rec eptors. LY339434 and (2S,4R)-4-methylglutamic acid showed selectivity in ligand binding studies for kainate receptors over AMPA receptors. W ithin the kainate class of glutamate receptors, LY339434 showed select ivity for GluR5 over GluR6 whereas (2S,4R)-4-methylglutamic acid showe d high affinity for both GluR5 and GluR6 kainate receptors. Examinatio n of the functional activity of LY339434 and (2S,4R)-4-methylglutamic acid showed that both compounds evoked inward currents in dorsal root ganglion neurons (DRG) with estimated EC50 values of 0.8 +/- 0.2 mu M and 0.17 +/- 0.04 mu M, respectively. In GluR5 expressing HEK 293 cell s, LY339434 evoked inward currents with an estimated EC50 value of 2.5 +/- 0.9 mu M but had little effect on GluR6 expressing cells at conce ntrations less than 100 mu M. LY339434 was a weak AMPA receptor agonis t (EC50 values > 300 mu M) as determined by activity in acutely isolat ed cerebellar Purkinje neurons. LY339434 and (2S,4R)-4-methylglutamic acid:had agonist activity at NMDA receptors studied in cultured hippoc ampal neurons with EC(50)s of 2.5 mu M and 11.7 mu M, respectively. Th ese results indicate that both LY339434 and (2S,4R)-4-methyl glutamic acid may be useful pharmacological tools for the examination of kainat e receptors. (C) 1998 Elsevier Science Ltd. All rights reserved.