LY339434, a GluR5 kainate receptor agonist

Small, Bryce A.; Thomas, J W; Kemp, Mark I.; Hoo, Ken H.; Ballyk, Barbara A.; Deverill, Michelle; Ogden, Ann Marie L.; Rubio, Alberto Pérez; Pedregal, Concepciòn; Bleakman, David

doi:10.1016/s0028-3908(98)00122-1

Cited by 41 publications

(31 citation statements)

References 27 publications

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“…(2S,4R)-4-methylglutamate also binds to kainate receptors likely to be GluR5 and GluR6 receptor subtypes in rat brain membranes [61]. In accordance with these studies, (2S,4R)-4-methylglutamate shows binding affinity and functional agonist activity for both human GluR5 and GluR6 receptors [62]. Other functional studies have shown that (2S,4R)-4-methylglutamate evokes nondesensitizing currents in the presence of concanavalin A in rat DRG neurons [62,63] and cerebellar granule cells [64].…”

Section: Review Articlesupporting

confidence: 78%

Kainate receptor pharmacology and physiology

Bleakman¹

1999

Cellular and Molecular Life Sciences (CMLS)

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Glutamate is the primary neurotransmitter in the central nervous system. One of the classes of ionotropic glutamate receptors is kainate receptors. Recent developments in the pharmacology of kainate receptors have resulted in the emergence of several selective agonists and antagonists. These compounds have allowed scientists to begin to probe the functional properties of these receptors in neurons and gain a better understanding of the role of these receptors in the nervous system.

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Section: Review Articlesupporting

confidence: 78%

Kainate receptor pharmacology and physiology

Bleakman¹

1999

Cellular and Molecular Life Sciences (CMLS)

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“…One potential example of such a subtypeselective ligand is LY339434. This compound is a kainate receptor agonist derivative of (2S,4R)-4-methylglutamate (Small et al, 1998). By replacing the methyl group with a bulky naphthalene ring on a propenyl linker at the 4-position of glutamate, GluR5 affinity is reduced 5-fold, whereas GluR6 affinity is reduced over 1000-fold.…”

Section: Discussionmentioning

confidence: 99%

Identification of Subunit- and Antagonist-Specific Amino Acid Residues in theN-Methyl-d-aspartate Receptor Glutamate-Binding Pocket

Kinarsky

Feng

Skifter

et al. 2005

J Pharmacol Exp Ther

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The resolved X-ray crystal structures of the glutamate-binding domain (S1/S2 domains) of the GluR2 and NR1 glutamate receptor subunits were used to model the homologous regions of the N-methyl-D-aspartate (NMDA) receptor's NR2 subunits. To test the predictive value of these models, all four stereoisomers of the antagonist 1-(phenanthren-2-carbonyl) piperazine-2,3-dicarboxylic acid (PPDA) were docked into the NR2B glutamate-binding site model. This analysis suggested an affinity order for the PPDA isomers of D-cis Ͼ L-cis Ͼ L-trans ϭ D-trans and predicted that the 2-position carboxylate group of the cis-PPDA isomers, but not of the trans-PPDA isomers, may be interacting with histidine 486 in NR2B. Consistent with these predictions, cis-PPDA displays a 35-fold higher affinity for NR2B-containing NMDA receptors than trans-PPDA. In addition, mutating NR2B's H486 to phenylalanine decreased cis-PPDA affinity 8-fold but had no effect on trans-PPDA affinity. In contrast, the NR2B H486F mutation increased the affinity of the typical antagonists CGS-19755 [(2R*,4S*)-4-phosphonomethyl-2-piperidine carboxylic acid] and 4-(3-phosphonopropyl) piperidine-2-carboxylic acid. In the NR1-based NR2 models, there were only four subunit-specific amino acid residues exposed to the ligand-binding pocket (and six in the GluR2-based models). These residues are located at the edge of the binding pocket, suggesting that large antagonists may be necessary for subtype specificity. Of these residues, mutational analysis and modeling suggest that A414, R712, and G713 (NR2B numbering) may be especially useful for developing NR2C-and NR2D-selective NMDA receptor antagonists and that residues A414 and T428 may determine subunit variations in agonist affinity.

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“…Ligand binding studies were performed on human recombinant AMPA and kainate receptors as described previously (Small et al, 1998). Cell membranes were prepared from frozen HEK293 cells expressing either recombinant AMPA or kainate receptors by resuspending the cells in ice-cold distilled water, sonicating, and centrifuging at 50,000g for 20 min.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Characterization of the Competitive GLU_K5 Receptor Antagonist Decahydroisoquinoline LY466195 in Vitro and in Vivo

Weiss¹,

Alt²,

Ogden³

et al. 2006

J Pharmacol Exp Ther

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The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLU K5 in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in vivo pharmacology of the competitive GLU K5 -selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR), the most potent GLU K5 antagonist described to date. Comparisons were made to the competitive GLU K5 /␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLU K5 receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 M)-induced currents with an IC 50 value of 0.045 Ϯ 0.011 M. In HEK293 cells transfected with GLU K5 , GLU K2 /GLU K5 , or GLU K5 /GLU K6 receptors, LY466195 produced IC 50 values of 0.08 Ϯ 0.02, 0.34 Ϯ 0.17, and 0.07 Ϯ 0.02 M, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID 100 value of 100 g/kg i.v. LY466195 was also efficacious in the c-fos migraine model, with a dose of 1 g/kg i.v. significantly reducing the number of Fos-positive cells in the rat nucleus caudalis after electrical stimulation of the trigeminal ganglion. Furthermore, LY466195 showed no contractile activity in the rabbit saphenous vein in vitro. The diethyl ester prodrug of LY466195 was also efficacious in the same PPE and c-fos models after oral administration at doses of 10 and 100 g/kg, respectively while having no N-methyl-D-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.Glutamate is the major excitatory neurotransmitter in the central nervous system and can act at three major types of ligand-gated ion channels that are defined by the activity of the subtype-selective agonists N-methyl-D-aspartate (NMDA), kainate, and ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) (Collingridge and Lester, 1989). Five kainate receptors subtypes have been cloned and classified as either high-affinity (GLU K1 and GLU K2 ) or lowArticle, publication date, and citation information can be found at

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LY339434, a GluR5 kainate receptor agonist

Cited by 41 publications

References 27 publications

Kainate receptor pharmacology and physiology

Kainate receptor pharmacology and physiology

Identification of Subunit- and Antagonist-Specific Amino Acid Residues in theN-Methyl-d-aspartate Receptor Glutamate-Binding Pocket

Pharmacological Characterization of the Competitive GLU_K5 Receptor Antagonist Decahydroisoquinoline LY466195 in Vitro and in Vivo

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LY339434, a GluR5 kainate receptor agonist

Cited by 41 publications

References 27 publications

Kainate receptor pharmacology and physiology

Kainate receptor pharmacology and physiology

Identification of Subunit- and Antagonist-Specific Amino Acid Residues in theN-Methyl-d-aspartate Receptor Glutamate-Binding Pocket

Pharmacological Characterization of the Competitive GLUK5 Receptor Antagonist Decahydroisoquinoline LY466195 in Vitro and in Vivo

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Pharmacological Characterization of the Competitive GLU_K5 Receptor Antagonist Decahydroisoquinoline LY466195 in Vitro and in Vivo