Inhibition of ADP-induced human platelet aggregation by a new class of soluble guanylate cyclase activators capable of nitric oxide generation.
Diazetidine-di-N-oxide derivatives have been found capable of the nonenzymatic generation of nitric oxide by a principally new mechanism of nitric oxide splitting at physiological pH values. The effect of the synthesized compounds on human platelet soluble guanylate cyclase activity and ADP-induced human platelets aggregation were studied. Four of 7 derivatives studied exhibited a distinct correlation between the intensity of platelet guanylate cyclase activation, inhibition of platelets aggregation and acceleration of their disaggregation. The NO-dependent mechanism of guanylate cyclase activation and intraplatelet cGMP accumulation are suggested to be responsible for antiaggregatory/disaggregatory properties of the compounds used. Data presented allow us to regard 1,2-diazetidine-di-N-oxide derivatives as antiaggregatory agents of a new class.
Severina
I S
IS
Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow.
Belushkina
N N
NN
Grigoryev
N B
NB
D000244:Adenosine Diphosphate; D001384:Azetidines / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012995:Solubility
D001384:Azetidines; D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D006162:Guanylate Cyclase; D006152:Cyclic GMP