In Vitro Characterization of 5-Carboxyl-2,4-di-benzamidobenzoic Acid (NS3763), a Noncompetitive Antagonist of GLUK5 Receptors

Christensen, J. H.; Varming, Thomas; Ahring, Philip K.; Dyhring, Tino; Nielsen, Elsebet Ø.

doi:10.1124/jpet.103.062794

Cited by 37 publications

(37 citation statements)

References 35 publications

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“…1). In agreement with previous studies, NS3763 (10 M) antagonized homomeric GluR5 receptors (Christensen et al, 2004). Furthermore, we found that this compound acts exclusively on homomeric GluR5 and not on heteromeric receptors.…”

Section: Discussionsupporting

confidence: 81%

“…Two compounds have been described recently: LY382884 and NS3763, which appear to show certain specificity for KARs with different subunit compositions (Bortolotto et al, 1999;Smolders et al, 2002;Alt et al 2004;Christensen et al, 2004). To confirm that this was the case, we characterized these compounds in HEK293 cells expressing different combinations of KAR subunits.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we concluded that although LY382884 antagonizes native receptors containing GluR5 subunits (Alt et al, 2004), NS3763 would only act on homomeric GluR5 receptors (Christensen et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

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A Mosaic of Functional Kainate Receptors in Hippocampal Interneurons

Christensen¹,

Paternain²,

Selak³

et al. 2004

J. Neurosci.

118

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Although some physiological functions of kainate receptors (KARs) still remain unclear, recent advances have highlighted a role in synaptic physiology. In hippocampal slices, kainate depresses GABA-mediated synaptic inhibition and increases the firing rate of interneurons. However, the sensitivity to agonists of these responses differs, suggesting that the presynaptic and somatic KARs have a distinct molecular composition. Hippocampal interneurons express several distinct KAR subunits that can assemble into heteromeric receptors with a variety of pharmacological properties and that, in principle, could fulfill different roles. To address which receptor types mediate each of the effects of kainate in interneurons, we used new compounds and mice deficient for specific KAR subunits. In a recombinant assay, 5-carboxyl-2,4-di-benzamido-benzoic acid (NS3763) acted exclusively on homomeric glutamate receptor subunit 5 (GluR5), whereas 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl) 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884) antagonized homomeric GluR5 and any heteromeric combination containing GluR5 subunits. In hippocampal slices, LY382884, but not NS3763, was able to prevent kainate-induced depression of evoked IPSC. In contrast, neither prevented the concomitant increase in spontaneous IPSC frequency. The selectivity of these compounds was seen additionally in knock-out mice, such that they were inactive in GluR5 Ϫ/Ϫ mice but completely effective in GluR6 Ϫ/Ϫ mice. Our data indicate that in wild-type mice, CA1 interneurons express heteromeric GluR6 -KA2 receptors in their somatic compartments and GluR5-GluR6 or GluR5-KA2 at presynaptic terminals. However, functional compensation appears to take place in the null mutants, a new pharmacological profile emerging more compatible with the activity of homomeric receptors in both compartments: GluR5 in GluR6 Ϫ/Ϫ mice and GluR6 in GluR5 Ϫ/Ϫ mice.

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

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A Mosaic of Functional Kainate Receptors in Hippocampal Interneurons

Christensen¹,

Paternain²,

Selak³

et al. 2004

J. Neurosci.

118

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“…In functional studies at rat cerebral cortical neurons or dorsal root ganglion neurons, taken to be AMPA receptors and kainate receptors, respectively, NS102 had a K B of 114 M and 6 M, respectively (Wilding and Huettner, 1996). H͔kainate binding at recombinant human GluK1 and GluK2, respectively, expressed in HEK293 cells (Christensen et al, 2004b). (Löscher et al, 1999).…”

Section: Glutamate Receptor Ion Channelsmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Traynelis

Wollmuth

McBain

et al. 2010

Pharmacological Reviews

3,102

3,802

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“…For example, substitution at the 5-position of the uracil ring of N 3 -substituted willardiine derivatives generates potent and selective GluR5 KAR antagonists (Dolman et al, 2007). Noncompetitive antagonists also exist for GluR5-containing receptors (Valgeirsson et al, 2003;Christensen et al, 2004;Valgeirsson et al, 2004). A GluR6 antagonist has been described, but this compound, NS-102, has seen only limited use because of insolubility and questions regarding its subunit selectivity (Paternain et al, 1996;Lerma et al, 2001).…”

mentioning

confidence: 99%

Novel Analogs and Stereoisomers of the Marine Toxin Neodysiherbaine with Specificity for Kainate Receptors

Lash

Sanders

Akiyama

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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Antagonists for kainate receptors (KARs), a family of glutamategated ion channels, are efficacious in a number of animal models of neuropathologies, including epilepsy, migraine pain, and anxiety. To produce molecules with novel selectivities for kainate receptors, we generated three sets of analogs related to the natural marine convulsant neodysiherbaine (neoDH), and we characterized their pharmacological profiles. Radioligand displacement assays with recombinant ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and KARs demonstrated that functional groups at two positions on the neoDH molecule are critical pharmacological determinants; only binding to the glutamate receptor (GluR)5-2a subunit was relatively insensitive to structural modifications of the critical functional groups. NeoDH analogs in which the L-glutamate congener was disrupted by epimerization retained low affinity for GluR5-2a and GluR6a KAR subunits. Most of the analogs showed agonist activity in electrophysiological recordings from human embryonic kidney-T/17 cells expressing GluR5-2a KARs, similar to the natural convulsant neoDH. In contrast, 2,4-epi-neoDH inhibited glutamate currents evoked from both GluR5-2a and GluR6a receptor-expressing cells. Therefore, this compound represents the first compound to exhibit functional antagonist activity on GluR5-2a and GluR6a KAR subunits without concurrent activity on AMPA receptor subunits. Finally, binding affinity of the synthetic ligands for the GluR5-2a subunit closely correlated with their seizurogenic potency, strongly supporting a role for receptors containing this subunit in the convulsant reaction to KAR agonists. The analogs described here offer further insight into structural determinants of ligand selectivity for KARs and potentially represent useful pharmacological tools for studying the role of KARs in synaptic physiology and pathology.

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In Vitro Characterization of 5-Carboxyl-2,4-di-benzamidobenzoic Acid (NS3763), a Noncompetitive Antagonist of GLUK5 Receptors

Cited by 37 publications

References 35 publications

A Mosaic of Functional Kainate Receptors in Hippocampal Interneurons

A Mosaic of Functional Kainate Receptors in Hippocampal Interneurons

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Novel Analogs and Stereoisomers of the Marine Toxin Neodysiherbaine with Specificity for Kainate Receptors

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