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Human Trabecular Meshwork Cell Responses Induced by Bimatoprost, Travoprost, Unoprostone, and Other FP Prostaglandin Receptor Agonist Analogues

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Human Trabecular Meshwork Cell Responses Induced by Bimatoprost, Travoprost, Unoprostone, and Other FP Prostaglandin Receptor Agonist Analogues 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 PURPOSE. To determine the functional agonist potencies of the sopropyl ester prodrugs of prostaglandin F (FP)-class prosta- intraocular pressure (IOP)–lowering prostaglandin F (FP)–class Iglandin (PG) receptor agonists, including travoprost,1 latano- prostaglandin (PG) analogues (e.g., travoprost, latanoprost, bi- prost,2 and unoprostone isopropyl ester3 lower intraocular matoprost, and unoprostone isopropyl ester) in human trabec- pressure (IOP) in a number of mammalian species, including ular meshwork (h-TM) cells, by using phosphoinositide (PI) humans, and are used to treat ocular hypertension and glauco- turnover and intracellular Ca2ϩ ([Ca2ϩ] ) mobilization, and to ma.4 Another prostaglandin analogue prodrug, bimatoprost i 5 confirm the FP nature of these receptors by using an FP receptor (17-phenyl-trinor PGF2␣ ethyl amide), has also recently been antagonist, 11␤-fluoro-15-epi-15-indanyl-PGF ␣ (AL-8810). marketed for this indication. Even though putative FP recep- 2 6–8 2ϩ tors have been detected in the human ciliary muscle and METHODS. FP-receptor–mediated PI turnover and [Ca ] mobi- 9 i human trabecular meshwork (h-TM) cells, and an FP receptor lization were measured in h-TM cells by determining the accu- 10 3 3 from human ciliary body cDNA has been cloned, the detailed mulation of [ H]-inositol phosphates ([ H]-IPs) by anion-ex- pharmacologic characterization of the FP-receptor–mediated change chromatography and real-time fluorescence imaging, functional responses in these human ocular tissues and cells respectively. has not been described to date. In view of the paucity of this RESULTS. Various PG analogues concentration-dependently type of pharmacologic information, the purposes of our cur- stimulated production of [3H]-IPs in h-TM cells with the fol- rent studies were to determine the pharmacologic properties lowing agonist potencies (median effective concentration; of functionally coupled FP receptors in h-TM cells derived from ϭ Ͼ ϭ EC50): travoprost acid (EC50 2.4 nM) cloprostenol (EC50 several human donors without glaucoma, by using selective FP Ͼ Ϯ ϭ Ͼ 4.5 nM) ( )-fluprostenol (EC50 10.8 nM) latanoprost receptor agonist prodrugs such as latanoprost and travoprost ϭ Ͼ ϭ Ͼ and their respective free acids; to assess the ability of some of acid (EC50 34.7 nM) bimatoprost acid (EC50 112 nM) ϭ ϾϾ ϭ these FP receptor agonists to mobilize intracellular Ca2ϩ PGF2␣ (EC50 120 nM) unoprostone (UF-021; EC50 3280 Ͼ ϭ ϭ ([Ca2ϩ] ) in h-TM cells; and to determine the antagonist effects nM) S-1033 (EC50 4570 nM; all n 3–9). Prodrug deriv- i atives of these compounds exhibited the following potencies: of a novel FP-receptor antagonist 11␤-fluoro-15-epi-15-indanyl- 11 ϭ Ͼ PGF ␣ (AL-8810) at the h-TM FP receptors, to complete the travoprost (isopropyl ester; EC50 89.1 nM) latanoprost 2 ϭ Ͼ characterization of these receptors. To our knowledge, this (isopropyl ester; EC50 778 nM) bimatoprost (amide; ϭ represents the first such detailed study of FP receptor pharma- EC50 1410–6940 nM). Travoprost acid, PGF2␣, unoprostone, 2ϩ cology in h-TM cells expressing endogenous FP prostaglandin and S-1033 were tested in addition for [Ca ]i mobilization and found to have rapid and dose-dependent effects. The FP recep- receptors. tor-selective antagonist AL-8810 antagonized the (Ϯ)-fluproste- ϭ Ϯ ␮ nol–induced PI turnover in these cells (Ki 2.56 0.62 M) MATERIALS AND METHODS as well as that induced by bimatoprost and acids of latanoprost and travoprost. The agonist and antagonist potencies of the PG The reagents were obtained from the cited sources as follows: all tissue analogues from the PI turnover assays in h-TM cells correlated culture media, antibiotics, supplements, and trypsin-EDTA from Life well with PI turnover data obtained from the cloned human Technologies (Grand Island, NY); fetal bovine serum from Hyclone ciliary body FP receptor (r ϭ 0.92; P Ͻ 0.0001). (Logan, UT); formic acid, ammonium formate, LiCl, and type B gelatin from Sigma Chemical Co. (St. Louis, MO); [3H]-myo-inositol from Am- CONCLUSIONS. The pharmacology of the h-TM cell FP-receptor– 2ϩ ersham Corp. (Deerfield, IL); AG-1X8 anion-exchange resin from Bio- mediated PI turnover and [Ca ]i mobilization was defined Rad (Hercules, CA); scintillation fluid (Ecolume) from ICN Biomedicals using numerous synthetic (FP-selective) PG agonist analogues (Costa Mesa, CA); and bimatoprost, bimatoprost acid, (Ϯ)-fluprostenol and an FP receptor antagonist, AL-8810. Bimatoprost, tra- (1:1 mixture of [ϩ]) and [Ϫ] enantiomers), latanoprost, unoprostone, voprost, latanoprost, unoprostone isopropyl ester, and their and unoprostone isopropyl ester from Cayman Chemical Co. (Ann respective free acids were shown to be FP agonists in the h-TM Arbor, MI). Travoprost ([ϩ]-fluprostenol isopropyl ester), travoprost cells. (Invest Ophthalmol Vis Sci. 2003;44:715–721) DOI: free acid ([ϩ]), latanoprost acid, and AL-8810 were synthesized in the 10.1167/iovs.02-0323 Medicinal Chemistry Department of Alcon Research, Ltd. (Fort Worth, TX). Bimatoprost (Lumigan) was from Allergan, Inc. (Irvine, CA). S-1033 was generously provided by Shionogi (Osaka, Japan). FLIPR and the Ca2ϩ-sensitive dye kit were purchased from Molecular Devices From the Molecular Pharmacology Unit, Glaucoma Research, Al- con Research, Ltd., Fort Worth, Texas. Corp. (Menlo Park, CA). The h-TM cells were kindly provided by Mari Submitted for publication April 2, 2002; revised July 29, 2002; Engler, Therapeutic Target Research (Alcon Research, Ltd). accepted August 19, 2002. Commercial relationships policy: E, F. Cell Culture The publication costs of this article were defrayed in part by page 12 charge payment. This article must therefore be marked “advertise- The h-TM cells were obtained as previously described from dissected ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. TM explants of human donor eyes (from six different donors, ages 0.5, Corresponding author: Najam A. Sharif, Director and Head, Mo- 44, 51, 54, 80, and 85 years; all patients with no ocular disease history) lecular Pharmacology Unit, Alcon Research, Ltd. (R2-19), 6201 South kindly provided by various Eye Banks in the United States. The identity Freeway, Fort Worth, TX 76134-2099; [email protected]. of h-TM cells isolated from these explants was confirmed by a battery Investigative Ophthalmology & Visual Science, February 2003, Vol. 44, No. 2 Copyright © Association for Research in Vision and Ophthalmology 715 Downloaded from jov.arvojournals.org on 10/02/2021 716 Sharif et al. IOVS, February 2003, Vol. 44, No. 2 of biochemical and immunohistochemical techniques.12 The h-TM assays was defined as the compound concentration eliciting 50% of the cells were grown in DMEM with 1 g/L glucose supplemented with 100 maximal functional response induced by the agonist. Antagonist po- ␮ U/mL penicillin, 100 g/mL streptomycin, 2 mM L-glutamine, and 10% tency (equilibrium drug dissociation constants, Ki) was calculated with 11,17,18 ϭ ϩ fetal bovine serum. When confluent, these cells were subcultured and the following equation : antagonist Ki antagonist IC50/[1 11,17 seeded into uncoated 24-well plates for the phosphoinositide (PI)- (agonist concentration/agonist EC50)], where IC50 is the antagonist turnover experiments described. Cells were maintained in a humidified concentration causing 50% inhibition of the maximal functional re- atmosphere of 5% CO2 and 95% air, with two changes of fresh medium sponse) when the antagonistic effects of multiple concentrations of weekly. Cells from passages 1 to 8 were used in the studies. AL-8810 were titrated against a fixed concentration of the different 2ϩ agonists used in the current studies. [Ca ]i mobilization fluorescence PI Turnover Assay traces obtained from the FLIPR-based assays were amalgamated by PI turnover assays of phospholipase C activity were conducted as using the graphics software, to show the concentration-dependent previously described and involved the measurement of agonist-stimu- nature of the agonist-stimulated responses. Ϯ lated production of [3H]-inositol phosphates ([3H]-IPs) by anion-ex- All data were calculated and represented as the mean SEM. A change chromatography.13,14 Briefly, confluent h-TM cells (ϳ50,000/ Student’s unpaired t-test was used to determine statistical differences well) were exposed for 24 to 30 hours to 3.8 ␮Ci [3H]-myo-inositol (if any) between the agonist potencies of the various compounds Ͻ (18.3 Ci/mmol) in 1.0 mL of the respective serum-free medium to label tested. P 0.05 was set as the minimum acceptable level of signifi- the cell membrane phospholipids. Cells were then rinsed once with cance between data sets. DMEM/Ham’s F-12 containing 10 mM LiCl before incubation with the agonist (or solvent as the control) in 1.0 mL of the same medium for 1 hour at 37°C, after which the medium was aspirated and 1 mL cold 0.1 RESULTS M formic acid was added. When the antagonist effects of AL-8810 were studied, it was added to the cells 15 minutes before exposure to the PI turnover in the h-TM cells was linear at least up to 90 agonist and the assay continued for another hour in the presence of the minutes (data not shown) and thus a 60-minute incubation antagonist. The chromatographic separation of [3H]-IPs on an AG-1X8 protocol was chosen for the agonist-induced generation of 3 resin-containing column was performed as previously described,13,14 [ H]-IPs, to maximize the signal-to-noise ratio and to reduce with sequential washes with water and 50 mM ammonium formate, possible hydrolysis or degradation of the test compounds.
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