MCI-9042, a new antiplatelet agent is a selective S2-serotonergic receptor antagonist.
MCI-9042, (+/-)-1-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-3- (dimethylamino)-2-propyl hydrogen succinate hydrochloride inhibited platelet aggregation induced by collagen and secondary aggregation by ADP or epinephrine at 10(-6) M level in platelets of various species. The antiplatelet effect of MCI-9042 was potentiated in aggregation induced by a combination of serotonin with collagen. IC50 value of human platelet aggregation by the serotonin plus collagen was 1.0 x 10(-7) M. MCI-9042 inhibited serotonin release accompanied with collagen-induced platelet aggregation, while it did not affect serotonin uptake into platelet. MCI-9042 also potently inhibited the S2-serotonergic receptor-mediated contraction of rat caudal artery by serotonin in a competitive manner with a Ki value of 1.79 x 10(-8) M, while S1 receptor- or adrenergic receptor-mediated vasoconstriction was inhibited more weakly. Platelet adhesiveness, c-AMP level in platelets and the conversion of arachidonic acid to thromboxane A2 were not influenced by MCI-9042. These results suggest that MCI-9042 is a selective S2-serotonergic receptor antagonist, exhibiting the inhibition of S2-serotonergic potentiated platelet aggregation and the suppression of blood vessel constriction mediated by S2-serotonergic receptor.
Hara
H
H
Pharmaceuticals Laboratory, Research Center, Mitsubishi Kasei Corporation, Yokohama, Japan.
Osakabe
M
M
Kitajima
A
A
Tamao
Y
Y
Kikumoto
R
R
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D013386:Succinates / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D010975:Platelet Aggregation Inhibitors; D011985:Receptors, Serotonin; D013386:Succinates; C064294:sarpogrelate