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

Summary

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 × 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 K_i 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.

• References

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