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Abstract #8505 Published in IGR 5-1
Agonist activity of bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester and other prostaglandin analogs at the cloned human ciliary body FP prostaglandin receptor
Sharif NA; Kelly CR; Crider JYJournal of Ocular Pharmacology and Therapeutics 2002; 18: 313-324
The authors determined the agonist activity of a number of natural prostaglandins and prostaglandin analogues at the FP prostaglandin receptor cloned from a human ciliary body cDNA library using phosphoinositide (PI) turnover assays. Travoprost acid (EC50 = 3.2 ± 0.6 nM) was the most potent agonist in these cells followed by bimatoprost free acid (17-phenyl-trinor PGF2alpha; EC50 = 5.8 ± 2.6 nm), fluprostenol (EC50 = 6.1 ± 1.5 nm), and latanoprost free acid (PHXA85; EC50 = 54.6 ± 12.4 nm) which was 17-fold weaker (p < 0.001) than travoprost acid. Unoprostone and S-1033 were significantly (p < 0.001) weaker than travoprost acid. The amide prodrug, bimatoprost (EC50 = 694 ± 293 nm), activated this FP receptor with an intermediate potency. The isopropyl ester prodrugs, travoprost (EC50 = 42.3 ± 6.7 nm), latanoprost (EC50 = 126 ± 347 nm) and unoprostone isopropyl ester (EC50 = 9100 ± 2870 nm), also exhibited FP agonist activity. However, other compounds such as PGI2, bradykinin, histamine, and serotonin were inactive. The agonist activities of bimatoprost, unoprostone (UF-021), fluprostenol and acids of travoprost and latanoprost were antagonized by AL-8810 (11beta-fluoro- 15-epi-15-indanyl-PGF2alpha), an FP-receptor-selective antagonist (Ki = 1.0 - 2.1 μm; n = 3). These studies have demonstrated, for the first time, agonist activities of the currently known and marketed ocular hypotensive prostaglandin analogues at the cloned human ciliary body FP prostaglandin receptor.
Dr. N.A. Sharif, Molecular Pharmacology Unit, Alcon Research, Ltd, Fort Worth, Texas 76134-2099, USA. naj.sharif@alconlabs.com
Classification:
11.4 Prostaglandins (Part of: 11 Medical treatment)
