TY - JOUR T1 - The Methylglutamate, SYM 2081, is a Potent and Highly Selective Agonist at Kainate Receptors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 539 LP - 545 VL - 285 IS - 2 AU - Sean D. Donevan AU - Asim Beg AU - Jane M. Gunther AU - Roy E. Twyman Y1 - 1998/05/01 UR - http://jpet.aspetjournals.org/content/285/2/539.abstract N2 - The methylglutamate analog (2S,4R)-4-methylglutamate (SYM 2081) has been shown to potently displace high affinity [3H]kainate binding to cortical tissue and to recombinant kainate receptors, and to evoke rapidly desensitizing responses in electrophysiological recordings. We have used two electrode voltage clamp recordings to compare the potency and efficacy of SYM 2081 with other α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptor agonists at homomeric kainate and AMPA receptors expressed inXenopus oocytes. In the presence of concanavalin A to reduce agonist induced desensitization at kainate receptors, SYM 2081 was a potent agonist at homomeric kainate receptors composed of the GluR5 and GluR6 subunit, with an EC50 of 0.12 ± 0.02 and 0.23 ± 0.01 μM, respectively. SYM 2081 was highly selective for kainate receptors, the EC50 for activation of AMPA receptors composed of the GluR1 and GluR3 subunits was 132 ± 44 and 453 ± 57 μM, respectively. Other methylglutamate analogs were tested for kainate receptor agonist activity. Methylglutamate compounds with the methyl group at the 2 or 3 position of glutamate were inactive indicating that positioning of the methyl group at the 4 position was essential for agonist 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 potent than SYM 2081. These results indicate that SYM 2081 is a potent and selective agonist at kainate receptors, and thus will be a useful ligand for evaluating the role of kainate receptors in central nervous system function and disease. The American Society for Pharmacology and Experimental Therapeutics ER -