PHARMACOLOGICAL CHARACTERIZATION OF PROSTAGLANDIN-RELATED OCULAR HYPOTENSIVE AGENTS

The agonistic activity of the prostaglandin (PG)-related ocular hypote nsive agents, S-1033, UF-021 and PhXA34, to PG receptors was investiga ted by using in vitro tissue responses and binding of radio-labeled li gands to membranes. UF-021 and PhXA34, which are both 1-isopropyl este rified forms, were examined mainly in a free acid form. The agonistic activity to PGD2 and PGI2 receptors, examined using inhibition of ADP- induced aggregation of guinea pig platelets, was negligible for all th ree compounds. None showed substantial agonistic activity to TXA2 rece ptor, as determined from contractions of rat thorax aorta. PhXA34 show ed significant PGE2 agonistic activity. Among the three PGE2 receptor subtypes, the agonistic activity to EP1 and EP2 receptors was about 1/ 1000 and 1/2000 of PGE2, as determined from contraction of guinea pig longitudinal and circular ileum strips, respectively. The other two co mpounds showed little agonistic activity (<1/100 000 of PGE2) to these receptors. The agonistic activity to PGF2alpha receptors, as determin ed from contraction of cat iris sphincter strips, was substantial for S-1033 and PhXA34, being 1/45 and 1/2 of PGF2alpha, respectively, but weak for UF-021 (1/1600). To further investigate the affinity of the t hree compounds to PGE2 and PGF2alpha receptors, inhibition of [H-3]PGE 2 and [H-3]PGF2alpha binding was examined with membrane fractions of b ovine adrenal medulla which possesses EP3 type PGE2 receptors and bovi ne corpus luteum which has PGF2alpha receptors. The activity of PhXA34 for inhibiting [H-3]PGE2 binding was about 1/2000 of PGE2. S-1033 and UF-021 did not significantly inhibit [H-3]PGE2 binding within the ran ge examined (much less than1/2000 of PGE2). The activity to inhibit [H -3]PGF2alpha binding was strong for PhXA34 (about the same as that of PGF2alpha), while the activity for S-1033 and UF-021 was about 1/34 an d <1/280 of PGF2alpha, respectively. These results indicate that the s pecificity to PGF2alpha receptor is the highest for S-1033 followed by PhXA34 although the activity to this receptor is stronger for the lat ter compound. UF-021 has only a weak agonistic activity to PGF2alpha r eceptors.