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(Investigative Ophthalmology and Visual Science. 2003;44:715-721.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.02-0323
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Human Trabecular Meshwork Cell Responses Induced by Bimatoprost, Travoprost, Unoprostone, and other FP Prostaglandin Receptor Agonist Analogues

Najam A. Sharif, Curtis R. Kelly, and Julie Y. Crider

From the Molecular Pharmacology Unit, Glaucoma Research, Alcon Research, Ltd., Fort Worth, Texas.

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, 11ß-fluoro-15-epi-15-indanyl-PGF2{alpha} (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 (EC50 = 2.4 nM) > cloprostenol (EC50 = 4.5 nM) > (±)-fluprostenol (EC50 = 10.8 nM) > latanoprost acid (EC50 = 34.7 nM) > bimatoprost acid (EC50 = 112 nM) > PGF2{alpha} (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, PGF2{alpha}, 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 (Ki = 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.




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