INTRAOCULAR-PRESSURE EFFECTS OF SELECTIVE PROSTANOID RECEPTOR AGONISTS INVOLVE DIFFERENT RECEPTOR SUBTYPES ACCORDING TO RADIOLIGAND BINDING-STUDIES

The receptors involved in the ocular hypotensive activity of prostagia ndins (PG) E2 and F2alpha in dogs and monkeys was investigated by exam ining the effects of putative receptor selective agonists on intraocul ar pressure. A diverse variety of receptor selective agonists lowered intraocular pressure in these species. Thus, FP-receptor agonists (17- phenyl PGF2alpha, fluprostenol), agonists with potent activity at the EP3 receptor (MB 28767, sulprostone) and a prostanoid with activity at the EP2 receptor (11-deoxy PGE1) were all potent ocular hypotensives when administered as a single dose to dogs and monkeys or b.i.d. for 5 days in monkeys. These findings were regarded as surprising and promp ted us to re-examine some aspects of the current classification for pr ostanoid receptors. At present certain receptor subtypes, notably EP2, EP3 and FP receptors, are defined only according to the potency rank order for agonists. In these studies, we employed radioligand binding studies to determine the degree of competition between prostanoid agon ists claimed to be selective on the basis of functional assays. Compet ition studies with a diverse variety of prostanoids at the binding sit e for PGE2 and sulprostone on the myometrial plasma membrane prepared from the rat uterus were consistent with the presence of an EP3 recept or. Thus, EP3-receptor agonists (MB 28767 and sulprostone) potently in hibited PGE2 and sulprostone binding, whereas FP agonists (17-phenyl P GF2alpha, fluprostenol), a DP agonist (BW 245C), an EP1 antagonist (AH 6809), an EP2 agonist (AH 13205) and TP-receptor ligands (BM 13505, I -BOP) afforded little or no inhibition. Radioligand binding studies in plasma membrane preparations from the rat colon with 17-phenyl [H-3]P GF2alpha were consistent with the presence of an FP-receptor. 17-Pheny l [H-3]PGF2alpha was potently displaced by PGF2alpha, whereas only ver y weak competition at the receptor site was afforded by EP3 agonists ( MB 28767, sulprostone). These results are consistent with the existanc e of EP3 and FP receptors as distinct entities. These findings also im ply that the decrease in intraocular pressure produced by FP and EP3 a gonists results from stimulation of two independent subpopulations of prostanoid receptors.