Biological Activity of Designed Photolabile Metal Nitrosyls:  Light-Dependent Activation of Soluble Guanylate Cyclase and Vasorelaxant Properties in Rat Aorta

• Published in: Journal of medicinal chemistry 2006-12, Vol.49 (25), p.7325-7330
• Main Authors: Madhani, Melanie, Patra, Apurba K, Miller, Thomas W, Eroy-Reveles, Aura A, Hobbs, Adrian J, Fukuto, Jon M, Mascharak, Pradip K
• Format: Article
• Language: English
• Subjects: Animals; Aorta - drug effects; Aorta - physiology; Biological and medical sciences; Cardiovascular system; Cells, Cultured; Cyclic GMP - biosynthesis; Enzyme Activation; Guanylate Cyclase - chemistry; Guanylate Cyclase - isolation & purification; In Vitro Techniques; Iron; Light; Manganese; Medical sciences; Miscellaneous; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Nitric Oxide Donors - chemical synthesis; Nitric Oxide Donors - pharmacology; Nitric Oxide Donors - radiation effects; Organometallic Compounds - chemical synthesis; Organometallic Compounds - pharmacology; Organometallic Compounds - radiation effects; Pharmacology. Drug treatments; Rats; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - isolation & purification; Ruthenium; Soluble Guanylyl Cyclase; Structure-Activity Relationship; Vasodilation - drug effects; Vasodilator Agents - chemical synthesis; Vasodilator Agents - pharmacology; Vasodilator Agents - radiation effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0604629

The biological and pharmacological utility of nitric oxide (NO) has led to the development of many classes of NO-donor compounds as both research tools and therapeutic agents. Many donors currently in use rely on thermal decomposition or bioactivation for the release of NO. We have developed several photolabile metal-nitrosyl donors that release NO when exposed to either visible or UV light. Herein, we show that these donors are capable of activating the primary “NO receptor”, soluble guanylate cyclase (sGC), in a light-dependent fashion leading to increases in cGMP. Moreover, we demonstrate that these donors are capable of eliciting light-dependent increases of cGMP in smooth muscle cells and vasorelaxation of rat aortic smooth muscle tissue, all effects that are attributed to activation of sGC. The potential utility of these compounds as drugs and/or research tools is discussed.