title: Synthesis, pharmacological activity and nitric oxide generation by nitrate derivatives of theophylline.
abstract: Nitrates of theophylline derivatives - potential nitric oxide (NO) donors - were synthesized by esterification of 7-hydroxyalkyl theophylline derivatives with fuming nitric acid. The nitrates obtained were tested in-vitro in reactions with sulfydryl compounds at appropriately adjusted pH and temperature. Under the applied conditions, the synthesized compounds underwent decomposition to release NO, quantified using a polarographic method using a selective isolated (ISO-NO) sensor. The effects of dyphylline and proxyphylline and their new synthesized nitrates on arterial blood pressure (BP) were measured in spontaneously hypertensive (SH) rats. BP was measured in conscious SH rats using the tail-cuff method. Both short- and long-term administration of the xanthines tested significantly decreased systolic, diastolic and mean BP. The hypotensive effect of a single dose of nitrate dyphylline on mean BP was greater than that of the parent compound (P = 0.000012; P=0.000472 at 30 and 60 min post-dose, respectively), whereas proxyphylline and its nitrate derivative had similar activity. In rats treated with the tested compounds for 9 days twice daily, the decrease in BP persisted for at least 16 h after the last dose. Proxyphylline produced the most marked decrease in diastolic and mean BP. Among the xanthines examined, proxyphylline nitrate had the strongest hypotensive effect when administered in a single dose to animals pretreated with the same compound for 9 days. These results indicate that insertion of a nitrate group weakly modifies the hypotensive action of the studied xanthines in SH rats.
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, PL 90-151 Lodz, Poland. korzycka@pharm.am.lodz.pl
authors.forename: Lucyna
authors.initials: L
authors.lastname: Korzycka
authors.forename: Dorota
authors.initials: D
authors.lastname: Górska
mesh_terms: D000628:Aminophylline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004400:Dyphylline / Q000737:chemistry / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009566:Nitrates / Q000737:chemistry / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D013806:Theophylline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D009566:Nitrates; D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; C003237:proxyphylline; D004400:Dyphylline; D000628:Aminophylline; D009569:Nitric Oxide; D013806:Theophylline