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

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.