Lack of correlation between the observed stability and pharmacological properties of S-nitroso derivatives of glutathione and cysteine-related peptides

Citation
Jm. Tullett et al., Lack of correlation between the observed stability and pharmacological properties of S-nitroso derivatives of glutathione and cysteine-related peptides, BIOCH PHARM, 62(9), 2001, pp. 1239-1247
Citations number
40
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
62
Issue
9
Year of publication
2001
Pages
1239 - 1247
Database
ISI
SICI code
0006-2952(20011101)62:9<1239:LOCBTO>2.0.ZU;2-0
Abstract
S-Nitrosothiols (RSNOs) have been widely studied as donors of nitric oxide. In general, RSNOs are considered to be somewhat unstable; however, they ar e both potent vasodilators and inhibitors of platelet aggregation. In order to improve our understanding of the factors that determine the biological activity of RSNOs, the chemical stability and pharmacological activity of a series of RSNOs was determined. Results show that millimolar solutions of S-nitrosocysteine (SNOCys) and S-nitroso-L-cysteinylglycine (SNOCysGly) wer e the least stable, whereas S-nitroso-3-mercaptopropionic acid (SNOPROPA) a nd S-nitroso-N-acetyl-L-cysteine (SNONAC) were the most stable of the compo unds tested. Recent evidence suggests that RSNOs, such as SNONAC, are as un stable as SNOCys at micromolar concentrations. The decomposition of certain RSNOs is catalysed by trace amounts of copper (II) ions, with this phenome non being particularly evident for SNOCys and SNOCysGly. The decomposition of the more stable RSNOs, including S-nitroso-L-glutathione (SNOGSH) and L- gamma -glutamyl-L-cysteine (SNOGluCys), were not as sensitive to copper ion s. The decomposition of the stable RSNO, SNOGSH, was more rapid in the pres ence of excess thiol, whereas the decay of the unstable RSNO, SNOCys, was r educed with added thiol. All RSNOs tested inhibited platelet aggregation, r elaxed vascular smooth muscle, and inhibited cell growth in the nanomolar r ange, but their order of potency did not correlate with their chemical stab ility of millimolar solutions. It is apparent that the potency of an RSNQ i n a physiological situation will depend on the concentration of the compoun d present, the presence of trace metal ions such as copper, and the occurre nce of transnitrosation reactions. (C) 2001 Elsevier Science Inc. All right s reserved.