MODULATION OF THE KYNURENINE PATHWAY IN SEARCH FOR NEW NEUROPROTECTIVE AGENTS - SYNTHESIS AND PRELIMINARY EVALUATION OF (M-NITROBENZOYL)ALANINE, A POTENT INHIBITOR OF KYNURENINE-3-HYDROXYLASE

The synthesis of (o-nitrobenzoyl)-, (m-nitrobenzoyl)-, and (p-nitroben zoyl) alanine (o-, m-, and p-NBA), three new kynurenine analogues, and their evaluation as inhibitors of kynureninase and kynurenine-3-hydro xylase are reported. The most potent of these compounds, m-NBA, has an IC50 Of 0.9+/-0.1 mu M as an inhibitor of kynurenine-3-hydroxylase an d of 100+/-12 mu M as an inhibitor of kynureninase. When administered to rats, m-NBA significantly increases the concentration of kynurenine and kynurenic acid in the brain as well as in blood and in the liver. m-NBA has also been shown to increase the concentration of kynurenic acid in hippocampal extracellular fluid. This increase is associated w ith sedative and anticonvulsant activities, thus confirming the possib ility of antagonizing L-glutamate-mediated effects by modulating the k ynurenine pathway of L-tryptophan metabolism.