THIOKYNURENATES - A NEW GROUP OF ANTAGONISTS OF THE GLYCINE MODULATORY SITE OF THE NMDA RECEPTOR

Several substituted derivatives of kynurenic acid were tested on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex present in the guinea pig myenteric plexus, on the binding of [H-3]glycine and of [H-3]N-[1-(2-thienyl)cyclohexyl]piperidine ([H-3]TCP) to rat cortical membranes and on the depolarization of mice cortical wedges induced by NMDA or quisqualic acid (QA). Kynurenic acid derivatives, having a chlorine (Cl) or a fluorine atom in position 5 or 7 but not in position 6 or 8 had significantly lower IC50S than the parent compound when tested on the antagonism of glutamate-induced ileal contraction and in the glycine binding assay. A further significant increase in potency was obtained by substituting a thio group for the hydroxy group in position 4 of kynurenic acid: the IC50 was 160 +/- 20-mu-M of kynurenic acid and 70 +/- 15-mu-M of thiokynurenic acid in the myenteric plexus whereas these IC50S for glycine binding were 25 +/- 3 and 9 +/- 2-mu-M respectively. Several thiokynurenic acid derivatives were synthetized and showed an increased affinity for the glycine recognition site over the corresponding kynurenic acid derivatives. Glycine competitively antagonized the actions of the thiokynurenates in the ileum, in cortical wedges and on [H-3]TCP binding. In this preparation, 7-Cl-thiokynurenic acid had an IC50 of 8-mu-M for antagonizing 10-mu-M NMDA-induced depolarization while 50% of the 10-mu-M QA depolarization was antagonized at 300-mu-M. Thus thiokynurenic acid derivatives seem to be a new group of potent and selective antagonists of strychnine-insensitive glycine receptors.