THE METHYLGLUTAMATE, SYM-2081, IS A POTENT AND HIGHLY SELECTIVE AGONIST AT KAINATE RECEPTORS

The methylglutamate analog (2S,4R)-4-methylglutamate (SYM 2081) has be en shown to potently displace high affinity [H-3]kainate binding to co rtical tissue and to recombinant kainate receptors, and to evoke rapid ly desensitizing responses in electrophysiological recordings. We have used two electrode voltage clamp recordings to compare the potency an d efficacy of SYM 2081 with other ha-amino-3-hydroxy-5-methyl-4-isoxaz ole-propionate (AMPA)/kainate receptor agonists at homomeric kainate a nd AMPA receptors expressed in Xenopus oocytes. In the presence of con canavalin A to reduce agonist induced desensitization at kainate recep tors, SYM 2081 was a potent agonist at homomeric kainate receptors com posed of the GluR5 and GluR6 subunit, with an EC50 of 0.12 +/- 0.02 an d 0.23 +/- 0.01 mu M, respectively. SYM 2081 was highly selective for kainate receptors, the EC50 for activation of AM PA receptors composed of the GluR1 and GluR3 subunits was 132 +/- 44 and 453 +/- 57 mu M, r espectively. Other methylglutamate analogs were tested for kainate rec eptor agonist activity. Methylglutamate compounds with the methyl grou p at the 2 or 3 position of glutamate were inactive indicating that po sitioning of the methyl group at the 4 position was essential for agon ist activity. Of the four stereoisomers of 4-methylglutamate, SYM 2081 (2S,4R) was the most potent agonist. The (2R,4R) isomer was estimated to be 20-fold and the (2S,4S)-isomer approximately 1000-fold less pot ent than SYM 2081. These results indicate that SYM 2081 is a potent an d selective agonist at kainate receptors, and thus will be a useful li gand for evaluating the role of kainate receptors in central nervous s ystem function and disease.