Pharmacological Evidence for Thromboxane Receptor Heterogeneity—Implications for the Eye

ABSTRACT The pharmacological activity of two novel thromboxane A2 (TxA2)-mimetics, AGN191976 and AGN192093, was investigated in vitro, using standard organ bath assays and human platelets, to determine potency and selectivity at various prostanoid (PG-) receptors. The effects of these compounds on intraocular pressure in Beagle dogs were then compared with U-46619, a widely employed and structurally different TP-receptor agonist. AGN191976 and AGN192093 were highly potent TP-receptor agonists in the rat aorta (EC50 of 0.32 and 1.3 nM, respectively) and human myometrium. Both compounds were approximately 10 to 50 fold more potent than U-46619. These contractile responses could be blocked with a potent TP-receptor antagonist, SQ29548. In human platelets, AGN191976 (EC50=16.3 nM) and U-46619 (EC50=538.3 nM) potently stimulated aggregation (TP-receptor mediated effect), whereas AGN 192093 was a much weaker agonist (EC50=37.9 μM). AGN192093 was not a partial agonist in platelets, since it did not antagonize ag...