title: A diazen-1-ium-1,2-diolate analog of 7-azabenzobicyclo[2.2.1]heptane: synthesis, nitric oxide and nitroxyl release, in vitro hemodynamic, and anti-hypertensive studies.
abstract: 1-(7-Azabenzobicyclo[2.2.1]heptane)diazen-1-ium-1,2-diolate (16) was designed with the expectation that it would act as a dual nitric oxide (NO) and nitroxyl (HNO) donor that is not carcinogenic or genotoxic. Compound 16, with a suitable half-life (17.8 min) in PBS at pH 7, released NO (19%) and HNO (22%) during a 2h incubation in PBS at pH 7. In addition, compound 16 exhibited a significant in vitro positive inotropic effect, increased the rates of contraction and relaxation, and increased coronary flow rate, but did not induce a chronotropic effect. Furthermore, compound 16 (13.7 mg kg(-1), po dose) provided a significant reduction in the blood pressure of mice up to 3h post-drug administration. All these data suggest that compound 16 constitutes an attractive 'lead-compound' that could have potential applications to treat cardiovascular disease(s) such as congestive heart failure.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Atul
authors.initials: A
authors.lastname: Bhardwaj
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.forename: Fenghua
authors.initials: F
authors.lastname: Yang
authors.forename: John M
authors.initials: JM
authors.lastname: Seubert
authors.forename: Edward E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006536:Heptanes / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007094:Imides / Q000737:chemistry; D051379:Mice; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000959:Antihypertensive Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006536:Heptanes; D007094:Imides; D009589:Nitrogen Oxides; C000109:azabicyclane; D009569:Nitric Oxide; C039900:nitroxyl; C038867:diazene