Agonist activity of bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester and other prostaglandin analogs at the cloned human ciliary body FP prostaglandin receptor.
We have determined the agonist activity of a number of natural prostaglandins and prostaglandin analogs 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 = 9,100 +/- 2,870 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 microM; n = 3). These studies have demonstrated, for the first time, agonist activities of the currently known and marketed ocular hypotensive prostaglandin analogs at the cloned human ciliary body FP prostaglandin receptor.
Sharif
N A
NA
Molecular Pharmacology Unit, Alcon Research, Ltd, Fort Worth, Texas 76134-2099, USA. naj.sharif@alconlabs.com
Kelly
C R
CR
Crider
J Y
JY
D000577:Amides; D000069580:Bimatoprost; D002478:Cells, Cultured; D002924:Ciliary Body / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003001:Cloning, Molecular; D003008:Cloprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000077338:Latanoprost; D008055:Lipids / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology*; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000069557:Travoprost
D000577:Amides; D008055:Lipids; D011453:Prostaglandins; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; D003008:Cloprostenol; C072630:isopropyl unoprostone; D000077338:Latanoprost; D015237:Dinoprost; D000069580:Bimatoprost; D000069557:Travoprost