ANTIAGGREGANT AND ANTIVASOSPASTIC PROPERTIES OF THE NEW THROMBOXANE A(2) RECEPTOR ANTAGONIST SODIUM NYL]AMINO]METHYL]CYCLOPENTYL]METHYL]BENZENEACETATE

LCB 2853 (sodium 4-[[1-[[[(4-chlorophenyl) sulfonyl] amino] methyl] cy clopentyl] methyl] benzeneacetate, CAS 141335-11-7) was demonstrated t o be a potent thromboxane A(2)/prostaglandin H-2 (TXA(2)/PGH(2)) recep tor antagonist in in vitro, ex vivo and in vivo experiments. The speci fic mechanism of action was studied in [H-3] SQ 29548 receptor binding studies (pKi = 7.93) and was shown to be of competitive nature in U 4 6619-induced platelet aggregation (pA(2) = 6.82). TXA(2)-dependent pla telet rich plasma (PRP) aggregation (U 46619, arachidonic acid (AA), c ollagen, ADP or serotonin second phase) was inhibited in vitro in huma ns (IC50: 0.037-0.65 mu mol/l) and different animal species, as well a s ex vivo i.v. rat and p.o. guinea-pid AA-induced aggregation (ED(50) = 48 and 57 mu g/kg). The U 46619-induced contractions of aorta, cauda l artery and trachea were inhibited in a dose-dependent way (IC50 = 0. 07, 0.02 and 0.5 mu mol/l respectively). In vivo, both against platele t aggregation and vasoconstriction, LCB 2853 showed an ED(50) lower th an 1 mg/kg i.v. in rat AA-induced thrombocytopenia or U 46619-induced hypertension (ED(50) = 0.25 and 0.16 mg/kg) as well as in AA-induced s udden death in the mouse (ED(50) = 0.44 mg/kg). The U 46619-induced br oncho-constriction was blocked after i.v. administration of LCB 2853 ( ED(50) = 18.4 mu g/kg). The duration of action observed in different m odels was 6 h by oral route and between 3 and 5 h by intravenous route . These properties in TXA(2)-dependent model led to further investigat ions of the antithrombotic activity of this novel TXA(2) antagonist.