Structure-activity relationships in kynurenine, diazepam and some putative endogenous ligands of the benzodiazepine receptors.
Kynurenine, an endogenous cerebral and peripheral neuroactive metabolite of 1-tryptophan, exerts stimulant and convulsant effects in mice, rats and frogs. In mice it (intracerebroventricularly, ICV) antagonized the anticaffeine effect of diazepam and in smaller doses potentiated its sedative action. In rats 1-kynurenine (ICV) potentiated the convulsant action of caffeine. The effect of pentylenetetrazol was not altered in either species. The convulsant effect of 1-kynurenine is the most resistant among various convulsants towards the protective action of diazepam. The structure of 1-kynurenine is similar to benzophenones, metabolites of diazepam, and has four structural fragments common with diazepam. Putative endogenous and non-endogenous ligands of the benzodiazepine receptors have from one to three of these common fragments. Among the antagonists of diazepam exhibiting stimulant and convulsant action ethyl-beta-carboline-3-carboxylate has the same four fragments, Ro 5-3663 and Ro 15-1788 have three and caffeine two. The most striking dissimilarity is a diazo-moiety (N-C-C-N or N-C=C-C=N) absent in the structure of 1-kynurenine. This moiety seems to be the most important for the binding to the benzodiazepine receptors. A role of each fragment and their combinations as well as the stereoconfiguration for the pharmacological activity is considered. It is suggested that 1-kynurenine is a putative endogenous modulator or, less probably, ligand of the benzodiazepine receptor of either type (most probably that which mediates anxiolytic action of benzodiazepines) or a part of this receptor. The benzodiazepine receptor might be a phylogenetically transformed kynurenine receptor. Highly selective antagonism of purines to 1-kynurenine suggests that it can modulate the function of the benzodiazepine receptors via purinergic mechanisms. Stimulant and convulsant action of 1-kynurenine can be related to a moiety of succinic acid (O=C-C-C-C=O) which is typical of quinolinic acid, the strongest endogenous convulsant among kynurenines, and aspartic acid, an excitatory amino acid. 1-Kynurenine is suggested to be an anxiogenic and convulsigenic endogenous factor.
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D012640:Seizures / Q000139:chemically induced; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; C038431:kynurenine receptor; D007737:Kynurenine; D003975:Diazepam