Derivatives of kynurenine as inhibitors of rat brain kynurenine aminotransferase

M. Varasi, A. Della Torre, F. Heidempergher, P. Pevarello, C. Speciale, P. Guidetti, D. R. Wells, R. Schwarcz

Research output: Contribution to journalArticlepeer-review

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 KYN's 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).

Original languageEnglish
Pages (from-to)11-21
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume31
Issue number1
DOIs
Publication statusPublished - 1996

Keywords

  • Enzyme inhibition
  • Kynurenic acid
  • Kynurenine
  • Kynurenine aminotransferase
  • Neuroprotection

ASJC Scopus subject areas

  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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