TY - JOUR T1 - (2<em>S</em>,4<em>R</em>)-4-Methylglutamic Acid (SYM 2081): A Selective, High-Affinity Ligand for Kainate Receptors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 422 LP - 427 VL - 280 IS - 1 AU - L.-M. Zhou AU - Z.-Q. Gu AU - A. M. Costa AU - K. A. Yamada AU - P. E. Mansson AU - T. Giordano AU - P. Skolnick AU - K. A. Jones Y1 - 1997/01/01 UR - http://jpet.aspetjournals.org/content/280/1/422.abstract N2 - 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 α-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) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid andN-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 α-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. The American Society for Pharmacology and Experimental Therapeutics ER -