New NO-Donors with Antithrombotic and Vasodilating Activities, IV: Chemical Reactivity of Nitrosimines and its Implications for their Pharmacologic Properties
✍ Scribed by Klaus Rehse; Klaus-Jürgen Schleifer; Eberhard Lüdtke; Eyke Böhme
- Book ID
- 102749457
- Publisher
- John Wiley and Sons
- Year
- 1994
- Tongue
- English
- Weight
- 582 KB
- Volume
- 327
- Category
- Article
- ISSN
- 0365-6233
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✦ Synopsis
Nitrososydnone-5-imines and Thiazole-2-nitrosimines are susceptible to photolytic cleavage of the =N-NO bond. This can be achieved with a tungsten lamp. In water the corresponding syndnone imine salts are formed in 90% yield at 37°C. Only at higher temp. (7OOC) ring opening is observed. In methanol about 25% of sydnones are obtained. On the other hand N O and N 2 0 were detected in the head space of the reaction vials when oxygen was excluded. The formation of N 2 0 from nitrososydnone imine was increased up to elevenfold by glutathione while the amount of NO' was decreased. In the presence of light and thiols soluble guanylate cyclase (s-GC) was stimulated. The results suggest that the nitroxylate anion NOplays an important role in the stimulation of S-GC.
Neue NO-Pharmaka mit antithrombotischen und gefiflerweiternden EigenschaBen, 4. Mitt.: Chemische Reaktivitiit von Nitrosiminen und ihr EinfluR auf pharmakologische Elgenschaften Die EN-NO-Bindung von Nitrososydnon-5-iminen and Thiazol-2-nitrosiminen wird in Losung durch Licht gespalten. Hierzu reicht eine normale Gltihlampe aus. In Wasser bei 37°C werden die entspr. Sydnoniminsalze in 90proz. Ausb. erhalten. Nur bei hoheren Temp. (70°C) wird auch Ringoffnung beobachtet. Werden methanolische Usungen bestrahlt, so entstehen auch 25% Sydnone. Unter 02-Ausschlu8 wurden in der Gasphase der Reaktionsge* NO' und N20 gefunden. In Gegenwart von Glutathion wird bis zu elfmal mehr Lachgas gebildet. wtihrend die Menge an NO' abnimmt. In Gegenwart von Licht und Thiol wird die Iosliche Guanylatyclase (s-GC) aktiviert. Die Ergebnisse sprechen fur eine bedeutende Rolle des Nitmxylations NO-bei der Stimulation der s-GC.
Recently we reported on the ability of several groups of nitrososydnone imines to inhibit the aggregation of blood
This effect in vivo led to an inhibition of the thrombus formation'), so that these compounds can be classified as antithrombotics. This effect is accompanied by vasodilating properties. Therefore, a therapeutical application in the prophylaxis of thrombosis in people with risk factor hypertension could be envisaged. During our in virro platelet studies we recognized that the in virro effect can only be shown when the platelet rich plasma is irradiated with visible light i.e. simply by the lamp of the Elvi 840 aggregometer. We speculated that the active metabolite formed thereby should be a NO species. We, therefore, started a thourough investigation to clarify the structure of the decomposition products.