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

Natural prostaglandins (PGs) such as PGD(2), PGE(2), PGF(2alpha), and PGI(2) 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), EPl (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 = 32-424 nM) and EPI (EC50 = 119 nM) receptors. Bimatoprost acid was less selective, exhibiting a relatively high affinity for the FP(K-i = 83 nM), EPl (Ki = 95 nM), and EP3 (K-i = 387 nM) receptors. Bimatoprost acid exhibited functional. activity at the EPI (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 muM to > 22 muM) 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.