SYM 2081

(2S,4R)-4-methylglutamic acid (SYM 2081): a selective, high-affinity ligand for kainate receptors.[Pubmed:8996224]

J Pharmacol Exp Ther. 1997 Jan;280(1):422-7.

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.

SYM-2081 a kainate receptor antagonist reduces allodynia and hyperalgesia in a freeze injury model of neuropathic pain.[Pubmed:10700603]

Brain Res. 2000 Mar 6;858(1):106-20.

Cold-freeze injury at -4 degrees C to the rat sciatic nerve produces mechanical allodynia and thermal hyperalgesia [M.A. Kleive, P.S. Jungbluth, J.A. Uhlenkamp, K.C. Kajander, Cold injury to rat sciatic nerve induces thermal hyperalgesia or analgesia, 8th World Congress on Pain, Vancouver, BC, Canada, August 1996 (Abstract).]. The NMDA receptor, an excitatory amino acid (EAA) receptor, appears to be involved in the development of allodynia and hyperalgesia following nerve injury. The role, if any, of the kainate receptor, another EAA receptor, remains unknown. In the current study, we evaluated whether (2S,4R)-4-methylglutamic acid (SYM-2081), a recently developed kainate receptor antagonist, attenuates increased responsiveness following cold injury to the sciatic nerve. During baseline testing, Sprague-Dawley rats were evaluated for frequency of withdrawal from von Frey filaments and latency of withdrawal from a radiant thermal source. Animals were then anesthetized, the left sciatic nerve was exposed, and the nerve was cooled to -4 degrees C for 15 min (n=24). For control rats (n=24), all procedures were identical except that the nerve was maintained at 37 degrees C. Testing resumed on the third day following surgery. On the fifth post-operative day, SYM-2081 (150 or 100 mg/kg), fentanyl citrate (0. 04 mg/kg) or vehicle was injected intraperitoneally. Injury to the rat sciatic nerve induced a significant increase in withdrawal frequency and a significant decrease in withdrawal latency (ANOVA, p<0.05). SYM-2081 and fentanyl significantly reduced these responses (p<0.05). These results suggest that kainate and opioid receptors are involved in the mechanical allodynia and thermal hyperalgesia that develop following cold injury to the sciatic nerve.

SYM 2081, an agonist that desensitizes kainate receptors, attenuates capsaicin and inflammatory hyperalgesia.[Pubmed:12738069]

Brain Res. 2003 May 30;973(2):252-64.

Excitatory amino acids acting at non-NMDA receptors contribute to transmission of nociceptive information. SYM 2081 ((2S,4R)-4-methyl glutamic acid) desensitizes kainate receptors, one subtype of non-NMDA receptors, to subsequent release of excitatory amino acids and thus may attenuate transmission of nociceptive information. To determine if SYM 2081 can prevent development of hyperalgesia, SYM 2081 (10, 50 or 100 mg/kg, i.p.) was administered prior to injection of capsaicin into the hindpaw of rats, which produces mechanical and heat hyperalgesia. To determine if SYM 2081 can reduce ongoing inflammatory hyperalgesia, SYM 2081 (10 or 100 mg/kg, i.p.) was administered after development of carrageenan-evoked hyperalgesia. Intraplantar injection of capsaicin produced an increase in hindpaw withdrawal frequency to mechanical stimuli (from 4+/-2 to 41+/-7%; mean+/-S.E.M.) and a decrease in withdrawal latency to heat (from 12.3+/-0.3 to 5.9+/-0.4 s) in rats that received vehicle. In contrast, rats that received SYM 2081 (100 mg/kg) prior to injection of capsaicin exhibited a lower hindpaw withdrawal frequency (18+/-4%) and a longer withdrawal latency (7.7+/-0.5 s). Intrathecal (1-100 microg/5 microl), but not intraplantar (10 or 100 microg/50 microl), injection of SYM 2081 attenuated the development of capsaicin-evoked heat hyperalgesia suggesting that SYM 2081's antihyperalgesic effects were due to its central effects. Furthermore, SYM 2081 completely reversed ongoing carrageenan-evoked mechanical hyperalgesia and partially (approximately 50%) reversed ongoing heat hyperalgesia. The present study demonstrates that administration of a high-potency ligand that selectively desensitizes kainate receptors attenuates the development of mechanical and heat hyperalgesia and attenuates ongoing inflammatory hyperalgesia.

The methylglutamate, SYM 2081, is a potent and highly selective agonist at kainate receptors.[Pubmed:9580595]

J Pharmacol Exp Ther. 1998 May;285(2):539-45.

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 alpha-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 microM, 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 microM, 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.

Characterisation of kainate receptor mediated whole-cell currents in rat cultured cerebellar granule cells.[Pubmed:10219975]

Neuropharmacology. 1999 Mar;38(3):375-82.

Whole-cell voltage clamp recordings have been used to identify and characterise inward currents mediated by native kainate receptors in rat cultured cerebellar granule cells. While the selective AMPA receptor antagonist GYKI 53655 (50 microM) completely abolished inward currents evoked by AMPA (10-100 microM) in the presence of cyclothiazide (100 microM), kainate evoked currents in cells pretreated with concanavalin A (Con A) always showed a component (35-140 pA, n = 13) resistant to blockade. The majority (73+/-7%, n = 5) of GYKI 53655-resistant kainate-evoked inward currents remained in the presence of 100 microM AMPA. However, these currents were reversibly blocked by the competitive AMPA/kainate receptor antagonist NBQX (100 microM). (2S, 4R)-4-methylglutamate (SYM 2081, 10 microM) evoked inward currents in Con A treated cells (15-60 pA, n = 7), which were resistant to complete blockade by GYKI 53655 (50 microM) but antagonised by NBQX (100 microM). Kainate-evoked responses in the presence of GYKI 53655 (50 microM) had linear or slightly outwardly rectifying current-voltage (I-V) relationships in all cells examined (n = 5) and were resistant to blockade by Joro spider toxin (JsTx, 1 microM; n = 5). These results provide evidence that rat cultured cerebellar granule cells express functional kainate receptors made up of subunits which are edited at the Q/R site, and that SYM 2081 is an agonist at these native kainate receptors with a greater selectivity than kainate itself.

Desensitization of kainate receptors by kainate, glutamate and diastereomers of 4-methylglutamate.[Pubmed:9225313]

Neuropharmacology. 1997 Jun;36(6):853-63.

The potencies of kainate, glutamate and diastereomers of 4-methylglutamate were determined for activation and steady-state desensitization of GluR6 and dorsal root ganglion-type kainate receptors using whole-cell voltage clamp. In HEK293 cells expressing GluR6, all four diastereomers induced desensitizing inward currents at relatively high concentrations (> 50 microM), however, the 2S,4R diastereomer (2S,4R-4MG; SYM 2081) was approximately 100-fold more potent than the other three. The EC50 for receptor activation by 2S,4R-4MG (1.0 microM) was similar to that for kainic acid (1.8 microM), but 2S,4R-4MG was significantly more potent than kainate, glutamate or the other diastereomers of 4-methylglutamate at producing steady-state desensitization of GluR6 receptors. IC50s for desensitization quantified using a fixed concentration of kainate as a test agonist were 7.6, 31 and 667 nM for 2S,4R-4MG, kainate and glutamate, respectively. In addition, 2S,4R-4MG fully desensitized native kainate receptors (of the GluR5 subtype) in dorsal root ganglion neurons with an IC50 of 11 nM, compared to 3.4 microM for glutamate. For GluR6, recovery from desensitization displayed a similar time course for kainate and glutamate (tau = 3-4 s) but was roughly 20-fold slower for 2S,4R-4MG, which suggests that the rate of recovery is not entirely dependent on the affinity of ligand for the desensitized receptor. Following exposure to concanavalin A, application of kainate, glutamate and 2S,4R-4MG evoked very similar maximal currents that showed little or no desensitization. Lectin pretreatment produced a leftward shift in the concentration-response relationship for 2S,4R-4MG with an 11-fold reduction in the EC50; however, no significant change in the EC50 for kainate was observed. The characteristic of 2S,4R-4MG to potently and completely desensitize both recombinant GluR6 receptors and native receptors on dorsal root ganglion neurons suggests that this compound will be useful to study selective blockade of these receptors in the nervous system.

SYM 2081 is a high-affinity ligand and potent, selective agonist of kainate receptors, inhibits [3H]-kainate binding with an IC50 of 35 nM, almost 3000- and 200-fold selectivity for kainate receptors over AMPA and NMDA receptors respectively.

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