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Novel antagonists of the inhibitory glycine receptor derived from quinolinic acid compounds

V Schmieden, S Jezequel and H Betz

Department of Neurochemistry, Max-Planck-Institute for Brain Research, Frankfurt/Main, Germany.

Binding of the coagonist glycine to the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is potently antagonized by 2-carboxy-4- hydroxyquinolines. We show that closely related derivatives, 4-hydroxy- quinolines and 4-hydroxquinoline-3-carboxylic acids, antagonize the agonist response of the recombinant inhibitory glycine receptor (GlyR). In Xenopus laevis oocytes expressing the GlyR alpha 1 subunit, the chloride-substituted derivatives 5,7-dichloro-4-hydroxyquinoline-3- carboxylic acid and 7-chloro-4-hydroxyquinoline inhibited glycine currents in a mixed high affinity competitive and low-affinity noncompetitive fashion, whereas the related compounds 7-trifluoromethyl- 4-hydroxyquinoline-3-carboxylic acid and 7-trifluoromethyl-4- hydroxyquinoline showed purely competitive antagonism. Our data suggest a model of the pharmacophore of the GlyR that displays significant similarity to that proposed for the glycine binding site of the N- methyl-D-aspartate receptor.

Volume 50, Issue 5, pp. 1200-1206, 11/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1996 by the American Society for Pharmacology and Experimental Therapeutics