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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 25, 2004; DOI: 10.1124/jpet.103.062794

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Received for publication November 10, 2003.
Revised February 20, 2004.
Accepted for publication February 24, 2004.

In vitro characterization of NS3763, a non-competitive antagonist of GLUK5 receptors

Jeppe K Christensen 1, Thomas Varming 1, Philip K Ahring 1, Tino D Jorgensen 1, Elsebet O. Nielsen 1*

1 NeuroSearch A/S

* Address correspondence to: E-mail: eon{at}neurosearch.dk

Abstract

Accumulating preclinical data suggest that compounds that block the excitatory effect of glutamate on the kainate subtype of glutamate receptors may have utility for the treatment of pain, migraine and epilepsy. In the present study, the in vitro pharmacological properties of the novel glutamate antagonist NS3763 [5-carboxyl-2,4-di- benzamido-benzoic acid] are described. In functional assays in HEK293 cells expressing homomeric GLUK5 or GLUK6 receptors, NS3763 is shown to display selectivity for inhibition of domoate-induced increase in intracellular calcium mediated through the GLUK5 subtype (IC50 = 1.6 µM) of kainate receptors compared with the GLUK6 subtype (IC50 > 30 µM). NS3763 inhibits the GLUK5- mediated response in a non-competitive manner and does not inhibit [3H]{alpha}-amino-3-hydroxy-5-tertbutylisoxazole-4- propionic acid (ATPA)-binding to GLUK5 receptors. Furthermore, NS3763 selectively inhibits L-glutamate and domoate-evoked currents through GLUK5 receptors in HEK293 cells and does not significantly inhibit AMPA- or NMDA- induced currents in cultured mouse cortical neurons at 30 µM. This is the first report on a selective and non- competitive GLUK5 antagonist.


Key words: GLUK5, electrohysiology, glutamate, kainate, non-competitive antagonist, pharmacology


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