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Abstract #8494 Published in IGR 5-1
Human trabecular meshwork cell responses induced by bimatoprost, travoprost, unoprostone, and other FP prostaglandin receptor agonist analogues
Sharif NA; Kelly CR; Crider JYInvestigative Ophthalmology and Visual Science 2003; 44: 715-721
PURPOSE: To determine the functional agonist potencies of the intraocular pressure (IOP)-lowering prostaglandin F (FP)-class prostaglandin (PG) analogues (e.g., travoprost, latanoprost, bimatoprost, and unoprostone isopropyl ester) in human trabecular meshwork (h-TM) cells, by using phosphoinositide (PI) turnover and intracellular Ca2+ ([Ca2+](i)) mobilization, and to confirm the FP nature of these receptors by using an FP receptor antagonist, 11beta-fluoro-15-epi-15-indanyl-PGF2ALP (AL-8810). METHODS: FP-receptor-mediated PI turnover and [Ca2+](i) mobilization were measured in h-TM cells by determining the accumulation of [3H]-inositol phosphates ([3H]-IPs) by anion-exchange chromatography and real-time fluorescence imaging, respectively. RESULTS: Various PG analogues concentration-dependently stimulated production of [3H]-IPs in h-TM cells with the following agonist potencies (median effective concentration; EC50): travoprost acid (EC(50) = 2.4 nm) > cloprostenol (EC50 = 4.5 nm) > ( ±)-fluprostenol (EC50 = 10.8 nm) > latanoprost acid (EC50 = 34.7 nm) > bimatoprost acid (EC5) = 112 nm) > PGF2ALP (EC50 = 120 nm) >> unoprostone (UF-021; EC50 = 3280 nm) > S-1033 (EC50 = 4570 nm; all n = 3-9). Prodrug derivatives of these compounds exhibited the following potencies: travoprost (isopropyl ester; EC50 = 89.1 nm) > latanoprost (isopropyl ester; EC50 = 778 nM) > bimatoprost (amide; EC50 = 1410-6940 nm). Travoprost acid, PGF2ALP, unoprostone, and S-1033 were tested in addition for [Ca2+](i) mobilization and found to have rapid and dose-dependent effects. The FP receptor-selective antagonist AL-8810 antagonized the (±)-fluprostenol-induced PI turnover in these cells (K(i) = 2.56 ± 0.62 μm) as well as that induced by bimatoprost and acids of latanoprost and travoprost. The agonist and antagonist potencies of the PG analogues from the PI turnover assays in h-TM cells correlated well with PI turnover data obtained from the cloned human ciliary body FP receptor (r = 0.92; p < 0.0001). CONCLUSIONS: The pharmacology of the h-TM cell FP-receptor-mediated PI turnover and [Ca2+](i) mobilization was defined using numerous synthetic (FP-selective) PG agonist analogues and an FP receptor antagonist, AL-8810. Bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester, and their respective free acids were shown to be FP agonists in the h-TM cells.
Dr. N.A. Sharif, Molecular Pharmacology Unit, Glaucoma Research, Alcon Research, Ltd., Fort Worth, TX, USA
Classification:
11.4 Prostaglandins (Part of: 11 Medical treatment)
