title: (2S,4R)-4-methylglutamic acid (SYM 2081): a selective, high-affinity ligand for kainate receptors.
abstract: 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 alpha-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 approximately 32 and 19 nM, respectively) was comparable to that of kainic acid (IC50 values of approximately 13 and 28 nM, respectively). SYM 2081 was approximately 800- and 200-fold less potent as an inhibitor of radioligand binding to wild-type (rat forebrain) alpha-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 approximately 1 microM) 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 alpha-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 approximately 5-fold less potent than kainate (EC50 values of 325 and 70 microM, 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.
authors.affiliation: Symphony Pharmaceuticals, Inc., Malvern, Pennsylvania, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Zhou
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Gu
authors.forename: A M
authors.initials: AM
authors.lastname: Costa
authors.forename: K A
authors.initials: KA
authors.lastname: Yamada
authors.forename: P E
authors.initials: PE
authors.lastname: Mansson
authors.forename: T
authors.initials: T
authors.lastname: Giordano
authors.forename: P
authors.initials: P
authors.lastname: Skolnick
authors.forename: K A
authors.initials: KA
authors.lastname: Jones
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000494:pharmacology*; D006801:Humans; D007608:Kainic Acid / Q000378:metabolism; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D005971:Glutamates; D007608:Kainic Acid; D008024:Ligands; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C046105:4-methylglutamic acid