Agonist Activity of Bimatoprost,Travoprost,Latanoprost,Unoprostone Isopropyl Ester and Other Prostaglandin Analogs at the Cloned Human Ciliary Body FP Prostaglandin Receptor

Abstract

We have determined the agonist activity of a number of natural prostaglandins and prostaglandin analogs at the FP prostaglandin receptor cloned from a human ciliary body cDNA library using phosphoinositide (PI) turnover assays. Travoprost acid (EC₅₀ = 3.2 ± 0.6 nM) was the most potent agonist in these cells followed by bimatoprost free acid (17-phenyl-trinor PGF_2α; EC₅₀ = 5.8 ± 2.6 nM), fluprostenol (EC₅₀ = 6.1 ± 1.5 nM), and latanoprost 50 free acid (PHXA85; EC₅₀ = 54.6 ± 12.4 nM) which was 17-fold weaker (p < 0.001) than travoprost acid. Unoprostone and S-1033 were significantly (p < 0.001) weaker than travoprost acid. The amide prodrug, bimatoprost (EC₅₀= 694 ± 293 nM), activated this FP receptor with an intermediate potency. The isopropyl ester prodrugs, travoprost (EC₅₀ = 42.3 ± 6.7 nM), latanoprost (EC₅₀ = 126 ± 347 nM) and unoprostone isopropyl ester (EC₅₀ = 9100 ± 2870 nM), also exhibited FP agonist activity. However, other compounds such as PGI₂, bradykinin, histamine, and serotonin were inactive. The agonist activities of bimatoprost, unoprostone (UF-021), fluprostenol and acids of travoprost and latanoprost were antagonized by AL-8810 (11 β-fluoro-15-epi-15-indanyl-PGF_2α), an FP-receptor-selective antagonist (K_i = 1.0 – 2.1 μM; n = 3). These studies have demonstrated, for the first time, agonist activities of the currently known and marketed ocular hypotensive prostaglandin analogs at the cloned human ciliary body FP prostaglandin receptor.