New donors and acceptors of nitrogen oxide as a potential therapeutical agents

Abstract

The synthesis of new donors and acceptors of nitrogen oxide is described. New lipophilic nitronylnitroxyl radicals (NNR) that act as paramagnetic scavengers of nitrogen oxide are synthesized and characterized. The purity of the preparations is determined, and their structures are confirmed. The lipophilicity of the radicals is tested by ESR spectroscopy. The incorporation into lipid multilayers is shown to protect NNR from reduction in biological samples, while their ability to scavenge nitrogen oxide and form iminonitroxyl radicals is retained. A decreased rate of NNR reduction under these conditions substantially enhances their effectiveness as paramagnetic acceptors of nitrogen oxide in biological systems. The synthesis of a new hydrophilic NO donor, 3-bromo-3,4-dihydro-4,4-dimethyl-4-(2-pyridyl)-diazet-1,2-dioxide (DDpyr), is described. The constants of DDpyr decomposition in tris-HCl buffer (pH 7.5) and in DMSO are determined (4.5 x 10(-6) and 0.5 x 10(-6) s-1, respectively). A substantially higher rate of of DDpyr decomposition in buffer, compared with the decomposition rates determined previously for some diazetines, makes DDpyr a prospective candidate for the use in aqueous media. It is found in experiments on perfused rat caudal artery that DDpyr is an effective vasodilator. Intraperitoneal injection of DDpyr to hereditarily hypertensive rats (ISIAH line) at doses of 100-200 micrograms/kg body mass considerably diminishes their systolic arterial pressure.