Oxygen and oxidation promote the release of nitric oxide from sydnonimines.
The antianginal effect of sydnonimines is believed to be due to the release of nitric oxide (NO) from inactive prodrugs. The first step in the transformation of the sydnonimine SIN-1 is the hydroxyl ion-dependent conversion to SIN-1A that occurs almost immediately at neutral pH. However, the subsequent process of NO release from SIN-1A is not yet understood. Therefore, the spontaneous degradation of SIN-1A in aqueous solutions was studied by chemical and pharmacological means. Measurement of the oxygen content of a freshly prepared SIN-1A solution revealed a rapid decrease of the oxygen concentration. The oxygen-consuming process was accompanied by a decrease in SIN-1A concentration and a progressive formation of NO and SIN-1C. SIN-1A was stable under nitrogen, labile under air, and very unstable under pure oxygen. Thus, oxygen is an important reactant in the decomposition of SIN-1A. The question of whether or not oxygen is essential for NO release was studied by investigating the effect of other oxidants. The oxidants potassium hexacyanoferrate, cupric sulfate, and lead tetraacetate augmented the conversion of SIN-1A to SIN-1C and increased the relaxing effect on isolated pulmonary arteries used to bioassay NO. Therefore, an oxidative process is essential for the release of NO from sydnonimines.
Bohn
H
H
Department of Medicinal Chemistry, Cassella AG, Frankfurt/Main, F.R.G.
Schönafinger
K
K
D001681:Biological Assay; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D008981:Molsidomine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D009569:Nitric Oxide / Q000493:pharmacokinetics*; D009602:Nitrosamines / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D011651:Pulmonary Artery; D014665:Vasodilator Agents / Q000493:pharmacokinetics
D009602:Nitrosamines; D014665:Vasodilator Agents; C006006:N-nitrosomorpholinoaminoacetonitrile; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine