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 microM), 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 microM). 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.
Ferioli
R
R
Center for Cardiopulmonary Pharmacology, University of Milano, Italy.
Folco
G C
GC
Ferretti
C
C
Gasco
A M
AM
Medana
C
C
Fruttero
R
R
Civelli
M
M
Gasco
A
A
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
D006454:Hemoglobins; D009573:Nitrites; D010069:Oxadiazoles; D010108:Oxyhemoglobins; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D009638:Norepinephrine