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Thromboxane (TXA2) activates the T prostanoid (TP) receptor. Prostaglandin E2 (PGE2) activates four E prostanoid (EP) receptors, EP1-4. AH-23848 is a dual antagonist of TP1 and EP4 receptors. It originally was found to inhibit TXA2-induced platelet aggregation (IC50 = 0.26 μM) and the contraction of human bronchial smooth muscle induced by the TP agonist U-46619. AH-23848 was subsequently demonstrated to impair PGE2-mediated relaxation of piglet saphenous vein by antagonizing the PGE2 receptor EP4. Through inhibiting EP4, it likewise suppresses serum-induced cAMP generation, cyclin A synthesis, as well as the proliferation of fibroblasts, as well as reduces metastasis in a murine model of metastatic breast cancer.
1 Brittain, R.T., Boutal, L., Carter, M.C., et al. AH23848: A thromboxane receptor-blocking drug that can clarify the pathophysiologic role of thromboxane A2. Circulation 72 1208-1218 (1985). 2 Coleman, R.A., Grix, S.P., Head, S.A., et al. A novel inhibitory prostanoid receptor in piglet saphenous vein. Prostaglandins 47 151-168 (1994). 3 Coleman, R.A., Sheldrick, R.L.G. Prostanoid-induced contraction of human bronchial smooth muscle is mediated by TP-receptors. Br J Pharmacol 96 688-692 (1989). 4 Sanchez, T., Moreno, J.J. Role of EP1 and EP4 PGE2 subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation. Am J Physiol Cell Physiol 282 C280-C288 (2002). 5 ma, X., Kundu, N., Rifat, S., et al. Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis. Cancer Res 66(6) 2923-2927 (2006).
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