Siguazodan (SKF 94836) is a potent, selective and orally active phosphodiesterase III (PDE-III) inhibitor with an IC50 of 117 nM. Siguazodan increases cAMP accumulation in intact platelets with an EC50 of 18.88 μM. Siguazodan also inhibits phenylephrine-induced 5-HT release with an IC50 value of 4.2 μM[1][2][3].
Siguazodan selectively inhibits the major cyclic AMP-hydrolysing PDE in human platelet supernatants. The inhibited enzyme has been variously termed cyclic GMP-inhibited PDE or PDE-III. In platelet-rich plasma (PRP), Siguazodan inhibits U46619-induced aggregation more potently than that induced by adenosine 5'-diphosphate (ADP), and collagen. Treatment of the PRP with Aspirin has no effect on the potency of Siguazodan. In washed platelets, Siguazodan increases cyclic AMP levels and reduces cytoplasmic free calcium. ADP decreases the ability of Siguazodan to raise cyclic AMP and this may explain its lower potency in inhibiting responses to ADP. Siguazodan has anti-platelet actions over the same concentration range that it is an inotrope and vasodilator[2].
Siguazodan is a potent, selective inhibitor of phosphodiesterase III that has positive inotropic and vasodilating actions in various laboratory animals and is orally active with a long duration of action in conscious dogs[2].
[1]. Tang KM, et al. Photoaffinity labelling of cyclic GMP-inhibited phosphodiesterase (PDE III) in human and rat platelets and rat tissues: effects of phosphodiesterase inhibitors. Eur J Pharmacol. 1994 Jun 15;268(1):105-14. [2]. Murray KJ, et al. The effects of siguazodan, a selective phosphodiesterase inhibitor, on human platelet function. Br J Pharmacol. 1990 Mar;99(3):612-6. [3]. Freitag A, et al. Phosphodiesterase inhibitors suppress alpha2-adrenoceptor-mediated 5-hydroxytryptamine release from tracheae of newborn rabbits. Eur J Pharmacol. 1998 Jul 31;354(1):67-71.