The synthesis of (o-nitrobenzoyl)-, (m-nitrobenzoyl)-, and (p-nitrobenzoyl)alanine (o-, m-, and p-NBA), three new kynurenine analogues, and their evaluation as inhibitors of kynureninase and kynurenine-3-hydroxylase are reported. The most potent of these compounds, m-NBA, has an IC50 of 0.9 +/- 0.1 microM as an inhibitor of kynurenine-3-hydroxylase and of 100 +/- 12 microM 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 with sedative and anticonvulsant activities, thus confirming the possibility of antagonizing L-glutamate-mediated effects by modulating the kynurenine pathway of L-tryptophan metabolism.

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 / R. Pellicciari; B. Natalini; G. Costantino; M.R. Mamhoud; L. Mattoli; B. Sadeghpour; F. Moroni; A. Chiarugi; F. Carpenedo. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 37(1994), pp. 647-655. [10.1021/jm00031a015]

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

COSTANTINO, Gabriele;
1994

Abstract

The synthesis of (o-nitrobenzoyl)-, (m-nitrobenzoyl)-, and (p-nitrobenzoyl)alanine (o-, m-, and p-NBA), three new kynurenine analogues, and their evaluation as inhibitors of kynureninase and kynurenine-3-hydroxylase are reported. The most potent of these compounds, m-NBA, has an IC50 of 0.9 +/- 0.1 microM as an inhibitor of kynurenine-3-hydroxylase and of 100 +/- 12 microM 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 with sedative and anticonvulsant activities, thus confirming the possibility of antagonizing L-glutamate-mediated effects by modulating the kynurenine pathway of L-tryptophan metabolism.
File in questo prodotto:
File Dimensione Formato  
jm00031a015.pdf

non disponibili

Tipologia: Documento in Post-print
Licenza: Creative commons
Dimensione 3.26 MB
Formato Adobe PDF
3.26 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2437250
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 132
  • ???jsp.display-item.citation.isi??? 137
social impact