A new class of furoxan derivatives as NO donors: mechanism of action and biological activity

1 The mechanism of action and biological activity of a series of R‐substituted and di‐R‐substituted phenylfuroxans is reported. 2 Maximal potency as vasodilators on rabbit aortic rings, precontracted with noradrenaline (1 μm), was shown by phenyl‐cyano isomers and by the 3,4‐dicyanofuroxan, characterized by a potency ratio 3–10 fold higher than glyceryl trinitrate (GTN). This effect was reduced upon coincubation with methylene blue or oxyhaemoglobin (10 μm). 3 The furoxan derivatives showing maximal potency as vasodilators were also able to inhibit collagen‐induced platelet aggregation, with IC50 values in the sub‐micromolar range. 4 The furoxan derivatives were able to stimulate partially purified, rat lung soluble guanylate cyclase; among the most active compounds, the 3‐R‐substituted isomers displayed a higher level of stimulatory effect than the 4‐R analogues. 5 Solutions (0.1 mm) of all the tested furoxans, prepared using 50 mm phosphate buffer, pH 7.4, (diluting 10 mm DMSO stock solutions) did not release nitric oxide (NO) spontaneously; however in presence of 5 mm l‐cysteine, a significant NO‐releasing capacity was observed, which correlated significantly with their stimulation of the guanylate cyclase activity.