AGN-191976 - A NOVEL THROMBOXANE-A(2)-MEMETIC WITH OCULAR HYPOTENSIVEPROPERTIES

The possible subdivision of thromboxane A(2)-sensitive (TP) receptors is currently a controversial subject. We report herein on a novel thro mboxane A(2) mimetic, AGN 191976, which has almost identical pharmacol ogical activity to the well-characterized prostaglandin H-2/thromboxan e A(2) (PGH(2)/TxA(2)) mimetic U-46619, but its effects on intraocular pressure are quite distinct from U-46619. Prostanoid receptor activit y was determined in vitro using different smooth muscle assays and pla telets. Intraocular pressure was measured tonometrically in ocular nor motensive Beagle dogs and Cynomolgus monkeys. Conjunctival microvascul ar permeability was determined in guinea pigs. Despite closely resembl ing U-46619 as a potent and selective TP receptor agonist, AGN 191976 was a potent ocular hypotensive in dogs and monkeys whereas U-46619 di d not lower IOP in either species. The ocular hypotensive effect of AG N 191976 in dogs was attenuated by pretreatment with the TP receptor a ntagonist SQ 29548. Thus, the ocular hypotensive effects of AGN 191976 are consistent with TP receptor stimulation. Both TxA(2)-mimetics cau sed plasma leakage in the guinea pig conjunctiva. The disparate activi ties of U-46619 and AGN 191976 in our studies suggest the existence of heterogeneous populations of TP-receptors in the eye.