Kynurenamines as Neural Nitric Oxide Synthase Inhibitors

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.

Reactions of the melatonin metabolite <I>N</I><SUP>1</SUP>-acetyl-5-methoxykynuramine (AMK) with the ABTS cation radical: identification of new oxidation products

“…Due to the lack of specific, highly sensitive detection procedures, physiological AMK concentrations are unknown to date, but AMK is also of particular interest in pharmacological terms, as a potent cyclooxygenase inhibitor, 30 specific down-regulator of cyclooxygenase 2 gene expression, 31 and inhibitor of neuronal NO synthase. 32 Up to now, AMK has been quantified only after administration of melatonin. When labeled melatonin was injected into the cisterna magna of rats, 35% of the radioactivity could be recovered as AMK, whereas the principal hepatic melatonin metabolite, 6-hydroxymelatonin, was not detectable.…”

Melatonin and its brain metabolite N1‐acetyl‐5‐methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice

“…Tris HCl and calcium chloride were obtained from Merck (Darmstadt, Germany). The synthesis of AMK has been described elsewhere (Entrena et al, 2005). All other chemicals of the purest available grade were obtained from SigmaAldrich (Madrid, Spain) unless otherwise specified.…”

NMR assignments and structural characterization of new thiourea and urea kynurenamine derivatives nitric oxide synthase inhibitors

“…The main differences between the 13 C chemical shifts of the previously kynurenamine derivatives [15] and the new kynurenamineureas and thioureas are the 13 C signals of the main chain (C-1 atom of the amides and the equivalent C-2 atom of the ureas or thioureas). The amide C-1 atom shows signals in a range of 167.4-176.4, whereas for the equivalent urea C-2 atom, the signals appear in a range of 158.5-160.0, and for the thiourea C-2 atom, the range is 180.7-184.3 ppm, according to similar compounds described in literature.…”