1 Prostacyclin (PGI 2 ) possesses various physiological functions, including modulation of nociception, inflammation and cardiovascular activity. Elucidation of these functions has been hampered by the absence of selective IP receptor antagonists. 2 Two structurally distinct series of IP receptor antagonists have been developed: 4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) and R-3-(4-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO3244794). 3 RO1138452 and RO3244794 display high affinity for IP receptors. In human platelets, the receptor affinities (pK i ) were 9.370.1 and 7.770.03, respectively; in a recombinant IP receptor system, pK i values were 8.770.06 and 6.970.1, respectively. 4 Functional antagonism of RO1138452 and RO3244794 was studied by measuring inhibition of carbaprostacyclin-induced cAMP accumulation in CHO-K1 cells stably expressing the human IP receptor. The antagonist affinities (pK i ) of RO1138452 and RO3244794 were 9.070.06 and 8.570.11, respectively. 5 Selectivity profiles for RO1138452 and RO3244794 were determined via a panel of receptor binding and enzyme assays. RO1138452 displayed affinity at I 2 (8.3) and PAF (7.9) receptors, while RO3244794 was highly selective for the IP receptor: pK i values for EP 1 (o5), EP 3 (5.38), EP 4 (5.74) and TP (5.09). 6 RO1138452 (1-10 mg kg , p.o.) significantly reduced carrageenan-induced mechanical hyperalgesia and edema formation. RO3244794 (1 and 10 mg kg À1 , p.o.) also significantly reduced chronic joint discomfort induced by monoiodoacetate. 7 These data suggest that RO1138452 and RO3244794 are potent and selective antagonists for both human and rat IP receptors and that they possess analgesic and anti-inflammatory potential.
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