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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 309; no. 3; pp. 1003 - 1010
• Main Authors: Christensen, Jeppe K, Varming, Thomas, Ahring, Philip K, Jørgensen, Tino D, Nielsen, Elsebet Ø
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.06.2004
• Subjects: Animals; Benzamides - pharmacology; Benzoates - pharmacology; Calcium - metabolism; Cells, Cultured; Excitatory Amino Acid Agonists - pharmacology; GluK2 Kainate Receptor; Humans; Mice; Receptors, AMPA - drug effects; Receptors, AMPA - metabolism; Receptors, Kainic Acid - antagonists & inhibitors; Receptors, Kainic Acid - physiology; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.062794

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 5-carboxyl-2,4-di-benzamido-benzoic acid (NS3763) are described. In functional assays in human embryonic kidney (HEK)293 cells expressing homomeric GLU K5 or GLU K6 receptors, NS3763 is shown to display selectivity for inhibition of domoate-induced increase in intracellular calcium mediated through the GLU K5 subtype (IC 50 = 1.6 μM) of kainate receptors compared with the GLU K6 subtype (IC 50 > 30 μM). NS3763 inhibits the GLU K5 -mediated response in a noncompetitive manner and does not inhibit [ 3 H]α-amino-3-hydroxy-5-tertbutylisoxazole-4-propionic acid binding to GLU K5 receptors. Furthermore, NS3763 selectively inhibits l -glutamate- and domoate-evoked currents through GLU K5 receptors in HEK293 cells and does not significantly inhibit α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid- or N -methyl- d -aspartate-induced currents in cultured mouse cortical neurons at 30 μM. This is the first report on a selective and noncompetitive GLU K5 antagonist.