In a little more than 10 years, the kynurenine metabolites of tryptophan have emerged from their former position as biochemical curiosities, to occupy a prominent position in research on the causes and treatment of several major CNS disorders. The pathway includes two compounds, quinolinic acid and kynurenic acid, which are remarkably specific in their pharmacological profiles: one is a selective agonist at receptors sensitive to NMDA, whereas the other is a selective antagonist at low concentrations at the strychnine-resistant glycine modulatory site associated with the NMDA receptor. It has been argued that these agents cannot be of physiological or pathological relevance because their normal extracellular concentrations, in the nanomolar range, are at least 3 orders of magnitude lower than those required to act at NMDA receptors. This is a facile argument, however, that ignores at least two possibilities. One is that both quinolinate and kynurenate may be present in very high concentrations locally at some sites in the brain that cannot be reflected in mean extracellular levels. Similar considerations apply to many neuroactive agents in the CNS. The fact that both compounds appear to be synthesised in, and thus emerge from, glial cells that are well recognised as enjoying a close physical and chemical relationship with some neurones in which the intercellular space may be severely restricted may support such a view. Certainly the realisation that NMDA receptors may not be fully saturated functionally with glycine would be consistent with the possibility that even quite low concentrations of kynurenate could maintain a partial antagonism at the glycine receptor. A second possibility is that there may be a subpopulation of NMDA receptors (or, indeed, for a quite different amino acid) that possesses a glycine modulatory site with a much lower sensitivity to glycine or higher sensitivity to kynurenate, making it more susceptible to fluctuations of endogenous kynurenine levels. Whatever the specific nature of their physiological roles, the presence of an endogenous selective agonist and antagonist acting at NMDA receptors must continue to present exciting possibilities for understanding the pathological basis of several CNS disorders as well as developing new therapeutic approaches. An imbalance in the production or removal of either of these substances would be expected to have profound implications for brain function, especially if that imbalance were present chronically.(ABSTRACT TRUNCATED AT 400 WORDS)
