title: The design of nitric oxide donor drugs: s-nitrosothiol tDodSNO is a superior photoactivated donor in comparison to GSNO and SNAP.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, P.O. Box 913, Dunedin, New Zealand.
authors.forename: Sweta
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, P.O. Box 913, Dunedin, New Zealand.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Sammut
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, P.O. Box 913, Dunedin, New Zealand. Electronic address: gregory.giles@otago.ac.nz.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Giles
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D055598:Chemical Phenomena; D015195:Drug Design; D006162:Guanylate Cyclase / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D055668:Photochemical Processes; D010778:Photochemotherapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000378:metabolism*; D026422:S-Nitrosoglutathione / Q000378:metabolism*; D026403:S-Nitrosothiols / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000071756:Soluble Guanylyl Cyclase; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D020030:Nitric Oxide Donors; D018160:Receptors, Cytoplasmic and Nuclear; D026403:S-Nitrosothiols; C000595178:tert-dodecane S-nitrosothiol; D026422:S-Nitrosoglutathione; D026423:S-Nitroso-N-Acetylpenicillamine; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
keywords: Cardiovascular; Drug design; Nitric oxide; S-nitrosothiol; Vasodilation