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Vol. 280, Issue 1, 422-427, 1997
Symphony Pharmaceuticals, Inc., Malvern, Pennsylvania (L.-M.Z.,
Z.-Q.G., A.M.C., P.E.M., T.G., K.A.J.),
Laboratory of Neuroscience,
National Institute of Diabetes and Diseases of the Kidney, National
Institutes of Health, Bethesda, Maryland (L.-M.Z., P.S.), and
Departments of
Neurology and Pediatrics, Washington University School
of Medicine, St. Louis, Missouri (K.A.Y.)
Glutamic acid activates ionotropic glutamate receptors that mediate
excitatory transmission in the central nervous system. The introduction
of a methyl group at position 4 of glutamic acid imparts selectivity
for kainate receptors, relative to other
(N-methyl-D-aspartate and
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) ionotropic glutamate receptors. Among the stereoisomers of 4-methylglutamic acid,
the potency of the (2S,4R)-isomer (SYM
2081) to inhibit [3H]kainic acid binding to both
wild-type (rat forebrain) and recombinant (GluR6) kainate receptors
(IC50 values of ~32 and 19 nM, respectively) was
comparable to that of kainic acid (IC50 values of ~13 and 28 nM, respectively). SYM 2081 was ~800- and 200-fold less potent as
an inhibitor of radioligand binding to wild-type (rat forebrain) -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and
N-methyl-D-aspartate receptors,
respectively. Preexposure of human embryonic kidney 293 cells stably
expressing GluR6 receptors to low concentrations of SYM 2081 (30-300
nM) resulted in a reversible blockade of the rapidly desensitizing
currents produced by kainate application. At higher concentrations, SYM
2081 (EC50 of ~1 µM) elicited kainate-like, rapidly
desensitizing, inward currents. Pretreatment of recombinant GluR6
receptors with concanavalin A both abolished the effect of SYM 2081 to
block kainate-induced currents and revealed nondesensitizing currents
induced by SYM 2081 alone. The latter observations provide strong
support for the hypothesis that SYM 2081 blocks kainate-induced currents through a process of agonist-induced desensitization. SYM 2081 also activated -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptor currents in primary cultures of cerebral cortex and,
consistent with data obtained by radioligand binding, was ~5-fold
less potent than kainate (EC50 values of 325 and 70 µM, respectively) in this measure. SYM 2081 is a high-affinity, selective, kainate agonist that may prove useful both as a probe to examine the
physiological functions of kainate receptors and as the prototype of a
novel class of therapeutic agents.
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