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.
Department of Neurochemistry, Max-Planck-Institute for Brain Research, Frankfurt/Main, Germany.
V
V
Schmieden
S
S
Jezequel
H
H
Betz
D000818:Animals; D002264:Carboxylic Acids / Q000378:metabolism / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology; D006846:Hydrocarbons, Halogenated / Q000378:metabolism / Q000494:pharmacology; D006912:Hydroxyquinolines / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D046911:Macromolecular Substances; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D002264:Carboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D006846:Hydrocarbons, Halogenated; D006912:Hydroxyquinolines; D046911:Macromolecular Substances; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine