Franco Heidempergher

Derivatives of kynurenine as inhibitors of rat brain kynurenine aminotransferase

Abstract The structural requirements of the catalytic site of kynurenine aminotransferase (KAT), the enzyme responsible for the conversion of l -kynurenine (KYN) to kynurenic acid (KYNA), were examined using analogs and derivatives of KYN. KYNA production from KYN was monitored in rat brain homogenates and brain tissue slices. Modification of KYNs acylalanine side chain or its ring amino group resulted in compounds which did not substantially affect KYNA synthesis. Ring chlorination in positions 3, 4, 5 and 6 yielded KYN analogs which interfered with KYNA production. l -5-Cl-KYN was the most active of the chlorinated kynurenines, and one of the most potent of several other 5-substituted kynurenines. l -5-Cl-KYN was an excellent substrate of KAT, yielding 6-Cl-KYNA. Finally, in kinetic studies, l -5-Cl-KYN ( K i = 5.4 μM) was found to have an approximately five times higher affinity to the enzyme than the natural substrate KYN ( K m = 28 μM).

Pyrrolo[3,2-c]quinoline derivatives: A new class of kynurenine-3-hydroxylase inhibitors

A series of pyrrolo[3,2-c]quinoline derivatives were synthesised and evaluated as inhibitors of selected enzymes of the kynurenine pathway. 7-Chloro-3-methyl-1H-pyrrolo[3,2-c]quinoline-4-carboxylic acid (7a) was found to be a relatively potent and selective inhibitor of kynurenine-3-hydroxylase (KYN-3-OHase). A molecular modelling study showed a good superimposition of 7a with PNU-156561 and kynurenine the natural substrate of KYN-3-OHase.