Kynurenamines as neural nitric oxide synthase inhibitors

J Med Chem. 2005 Dec 29;48(26):8174-81. doi: 10.1021/jm050740o.

Abstract

To find new compounds with potential neuroprotective activity, we have designed, synthesized, and characterized a series of neural nitric oxide synthase (nNOS) inhibitors with a kynurenamine structure. Among them, N-[3-(2-amino-5-methoxyphenyl)-3-oxopropyl]acetamide is the main melatonin metabolite in the brain and shows the highest activity in the series, with an inhibition percentage of 65% at a 1 mM concentration. The structure-activity relationship of the new series partially reflects that of the previously reported 2-acylamido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acids, endowed with a kynurenine-like structure. Structural comparisons between these new kinurenamine derivatives, kynurenines, and 1-acyl-3-(2-amino-5-methoxyphenyl)-4,5-dihydro-1H-pyrazole derivatives also reported confirm our previous model for the nNOS inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / enzymology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Kynuramine / analogs & derivatives*
  • Kynuramine / chemical synthesis
  • Kynuramine / pharmacology*
  • Kynurenine 3-Monooxygenase / antagonists & inhibitors
  • Molecular Conformation
  • Nitric Oxide Synthase Type I / antagonists & inhibitors*
  • Rats

Substances

  • Enzyme Inhibitors
  • Kynuramine
  • N-acetyl-5-methoxy kynurenamine
  • Nitric Oxide Synthase Type I
  • Kynurenine 3-Monooxygenase