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Vol. 285, Issue 2, 539-545, May 1998
Department of Neurology (S.D.D., R.E.T),
Anticonvulsant Drug
Screening Project (S.D.D), and
Human Molecular Biology and Genetics
Program (A.B., J.M.G., R.E.T), University of Utah, Salt Lake City,
Utah
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
-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainate
receptor agonists at homomeric kainate and AMPA receptors expressed in
Xenopus 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.
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