Real-time intracellular Ca2+ mobilization by travoprost acid, bimatoprost, unoprostone, and other analogs via endogenous mouse, rat, and cloned human FP prostaglandin receptors.
The ability of a number of prostaglandin F 2 alpha (PGF 2 alpha) analogs to mobilize intracellular Ca2+[Ca2+]iand to compete for [3H]PGF 2 alpha binding to prostaglandin F 2 alpha receptors (FP) was evaluated. Radioligand binding studies measuring displacement of [3H]PGF 2 alpha by a variety of FP prostaglandin analogs yielded the following rank order of affinities: travoprost acid [(+)-16-m-trifluorophenoxy tetranor PGF 2 alpha; (+)-fluprostenol] > bimatoprost acid (17-phenyl-trinor PGF 2 alpha) >> unoprostone (13,14-dihydro-15-keto-20-ethyl PGF 2 alpha) = bimatoprost (17-phenyl-trinor PGF 2 alpha ethyl amide) > or = Lumigan (bimatoprost ophthalmic solution). In FP functional studies, travoprost acid (EC50= 17.5-37 nM, n = 13), bimatoprost acid (EC50= 23.3-49.0 nM, n = 6-12), unoprostone (EC50= 306-1270 nM, n = 4-8), bimatoprost (EC50= 3070- 3940 nM, n = 4-9), and Lumigan (EC50= 1470-3190 nM, n = 5-9) concentration dependently stimulated [Ca2+]imobilization via the rat (A7r5 cells), mouse (3T3 cells), and cloned human ocular FP prostanoid receptors. The rank order of potency of these compounds at the FP receptor of the three species was similar and in good agreement with the determined binding affinities. The agonist effects of these compounds were concentration dependently blocked by the FP receptor-selective antagonist, AL-8810 (11beta-fluoro-15-epi-15-indanyl-tetranor PGF 2 alpha) (Ki= 0.6-1.3 microM). These studies have demonstrated that bimatoprost, unoprostone, and bimatoprost acid possess direct agonist activities at the rat, mouse, and human FP prostanoid receptor and that travoprost acid is the most potent of the synthetic FP prostaglandin analogs tested.
Kelly
Curtis R
CR
Molecular Pharmacology Unit, Pharmaceutical Products Research, Alcon Research, Ltd., Fort Worth, Texas 76134, USA. curtis.kelly@alconlabs.com
Williams
Gary W
GW
Sharif
Najam A
NA
D016475:3T3 Cells; D000577:Amides; D000818:Animals; D000069580:Bimatoprost; D002118:Calcium / Q000378:metabolism*; D003001:Cloning, Molecular; D003008:Cloprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008055:Lipids / Q000494:pharmacology*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011465:Prostaglandins, Synthetic / Q000494:pharmacology*; D051381:Rats; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D000069557:Travoprost
D000577:Amides; D008055:Lipids; D011465:Prostaglandins, Synthetic; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; C121227:AL 8810; D003008:Cloprostenol; C072630:isopropyl unoprostone; D015237:Dinoprost; D000069580:Bimatoprost; D002118:Calcium; D000069557:Travoprost