Department of Pharmacology and Toxicology, University of Otago, P.O. Box 913, Dunedin, New Zealand.
Department of Pharmacology and Toxicology, University of Otago, P.O. Box 913, Dunedin, New Zealand.
Eur J Pharmacol. 2014 Aug 15;737:168-76. doi: 10.1016/j.ejphar.2014.05.012. Epub 2014 May 22.
We have recently developed tert-dodecane S-nitrosothiol (tDodSNO) as a photoactivated nitric oxide (NO) donor. We here compare the potency of tDodSNO to S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylpenicillamine (SNAP), drugs which are also based upon the S-nitrosothiol functionality and have been extensively used for NO release studies. Photoactivation in vitro, at a clinically relevant light fluence rate (200W/m(2)), demonstrated that tDodSNO released much higher levels of NO than either GSNO or SNAP. When evaluated in an ex vivo aortic ring vasorelaxation assay, tDodSNO was also the only drug to exhibit a photodynamic response, with an 8 fold decrease in EC50 (8.1-1.0µM) upon irradiation. While both GSNO and SNAP induced NO dependent vasorelaxation at lower concentrations than tDodSNO (EC50׳s of 158 and 38nM respectively), this activity was due to their rapid metabolic decomposition, and could not be modulated by photoactivation. Additionally, tDodSNO׳s photodynamic response allowed vascular tone to be directly regulated by light intensity. Molecular modeling of drug properties suggested that these differences in activity could be attributed to a combination of an increase in tDodSNO׳s hydrophobicity, and substantial steric shielding of molecule׳s S-nitrosothiol group from solvent interactions. In conclusion, our study demonstrates that tDodSNO is currently the most effective known s-nitrosothiol for phototherapeutic applications.
我们最近开发了叔十二烷 S-亚硝酰化硫醇（tDodSNO）作为一种光激活的一氧化氮（NO）供体。我们在这里比较了 tDodSNO 与 S-亚硝基谷胱甘肽（GSNO）和 S-亚硝基-N-乙酰青霉胺（SNAP）的效力，这两种药物也是基于 S-亚硝酰硫醇功能，并被广泛用于 NO 释放研究。在体外的光激活实验中，在临床相关的光通量率（200W/m(2)）下，证明 tDodSNO 释放的 NO 水平明显高于 GSNO 或 SNAP。当在离体主动脉环血管舒张测定中进行评估时，tDodSNO 也是唯一表现出光动力反应的药物，在照射下 EC50（8.1-1.0µM）降低了 8 倍。虽然 GSNO 和 SNAP 在比 tDodSNO 更低的浓度下诱导了 NO 依赖性血管舒张（EC50‘分别为 158 和 38nM），但这种活性是由于它们的快速代谢分解，并且不能通过光激活来调节。此外，tDodSNO 的光动力反应允许通过光强度直接调节血管张力。药物性质的分子建模表明，这些活性差异可以归因于 tDodSNO 的疏水性增加，以及分子的 S-亚硝酰硫醇基团的大量空间位阻，使其免受溶剂相互作用的影响。总之，我们的研究表明，tDodSNO 是目前光治疗应用中最有效的已知 S-亚硝酰硫醇。
