Ocular Hypotensive FP Prostaglandin (PG) Analogs: PG Receptor Subtype Binding Affinities and Selectivities,and Agonist Potencies at FP and Other PG Receptors in Cultured Cells

Abstract

Natural prostaglandins (PGs) such as PGD₂, PGE₂, PGF2_2α, and PGI₂ exhibited the highest affinity for their respective cognate receptors, but were the least selective agents when tested in receptor binding assays. Travoprost acid ([+]-fluprostenol) was the most FP-receptor-selective compound, exhibiting a high affinity (K_i = 35 ± 5 nM) for the FP receptor, and minimal affinity for DP (K_i = 52,000 nM), EP₁ (K_i = 9540 nM), EP₃ (K_i = 3501 nM), EP₄ (K_i = 41,000 nM), IP (K_i > 90,000 nM), and TP (K_i = 121,000 nM) receptors. Travoprost acid was the most potent PG analog tested in FP receptor functional phosphoinositide turnover assays in the following cell types: human ciliary muscle (EC₅₀ = 1.4 nM), human trabecular meshwork (EC₅₀ = 3.6 nM), and mouse fibroblasts and rat aortic smooth muscle cells (EC₅₀ = 2.6 nM). Although latanoprost acid exhibited a relatively high affinity for the FP receptor (K_i = 98 nM), it had significant functional activity at FP (EC₅₀ = 32-124 nM) and EP₁ (EC₅₀ = 119 nM) receptors. Bimatoprost acid was less selective, exhibiting a relatively high affinity for the FP (K_i = 83 nM), EP₁ (K_i = 95 nM), and EP₃ (K_i = 387 nM) receptors. Bimatoprost acid exhibited functional activity at the EP₁ (EC₅₀ = 2.7 nM) and FP (EC₅₀ = 2.8-3.8 nM in most cells) receptors. Bimatoprost (nonhydrolyzed amide) also behaved as an FP agonist at the cloned human FP receptor (EC₅₀ = 681 nM), in h-TM (EC₅₀ = 3245 nM) and other cell types. Unoprostone and S-1033 bound with low affinity (K_i = 5.9 μM to > 22 μM) to the FP receptor, were not selective, but activated the FP receptor. In conclusion, travoprost acid has the highest affinity, the highest FP-receptor-selectivity, and the highest potency at the FP receptor as compared to the other ocular hypotensive PG analogs known so far, including free acids of latanoprost, bimatoprost, and unoprostone isopropyl ester.