MCI–9042, a New Antiplatelet Agent Is a Selective S2-Serotonergic Receptor Antagonist

Abstract

SummaryMCI–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 × 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 × 10–8 M, while Si 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.