title: Ocular hypotensive FP prostaglandin (PG) analogs: PG receptor subtype binding affinities and selectivities, and agonist potencies at FP and other PG receptors in cultured cells.
abstract: Natural prostaglandins (PGs) such as PGD2, PGE2, PGF2(2alpha), and PGI2 exhibited the highest affinity for their respective cognate receptors, but were the least selective agents when tested in receptor binding assays. Travoprost acid ([+]-fluprostenol) was the most FP-receptor-selective compound, exhibiting a high affinity (Ki = 35 +/- 5 nM) for the FP receptor, and minimal affinity for DP (Ki = 52,000 nM), EP1 (Ki = 9540 nM), EP3 (Ki = 3501 nM), EP4 (Ki = 41,000 nM), IP (Ki > 90,000 nM), and TP (Ki = 121,000 nM) receptors. Travoprost acid was the most potent PG analog tested in FP receptor functional phosphoinositide turnover assays in the following cell types: human ciliary muscle (EC50 = 1.4 nM), human trabecular meshwork (EC50 = 3.6 nM), and mouse fibroblasts and rat aortic smooth muscle cells (EC50 = 2.6 nM). Although latanoprost acid exhibited a relatively high affinity for the FP receptor (Ki = 98 nM), it had significant functional activity at FP (EC50 = 32-124 nM) and EP1 (EC50 = 119 nM) receptors. Bimatoprost acid was less selective, exhibiting a relatively high affinity for the FP (Ki = 83 nM), EP1 (Ki = 95 nM), and EP3 (Ki = 387 nM) receptors. Bimatoprost acid exhibited functional activity at the EP1 (EC50 = 2.7 nM) and FP (EC50 = 2.8-3.8 nM in most cells) receptors. Bimatoprost (nonhydrolyzed amide) also behaved as an FP agonist at the cloned human FP receptor (EC50 = 681 nM), in h-TM (EC50 = 3245 nM) and other cell types. Unoprostone and S-1033 bound with low affinity (Ki = 5.9 microM to > 22 microM) to the FP receptor, were not selective, but activated the FP receptor. In conclusion, travoprost acid has the highest affinity, the highest FP-receptor-selectivity, and the highest potency at the FP receptor as compared to the other ocular hypotensive PG analogs known so far, including free acids of latanoprost, bimatoprost, and unoprostone isopropyl ester.
authors.affiliation: Molecular Pharmacology Unit, Alcon Research, Ltd., Fort Worth, TX 76134-2099, USA. naj.sharif@alconlabs.com
authors.forename: N A
authors.initials: NA
authors.lastname: Sharif
authors.forename: C R
authors.initials: CR
authors.lastname: Kelly
authors.forename: J Y
authors.initials: JY
authors.lastname: Crider
authors.forename: G W
authors.initials: GW
authors.lastname: Williams
authors.forename: S X
authors.initials: SX
authors.lastname: Xu
mesh_terms: D000577:Amides; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D000069580:Bimatoprost; D001667:Binding, Competitive / Q000187:drug effects* / Q000502:physiology; D002417:Cattle; D002460:Cell Line; D002924:Ciliary Body / Q000166:cytology / Q000187:drug effects; D002986:Clinical Trials as Topic; D003008:Cloprostenol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects* / Q000502:physiology; D007668:Kidney / Q000166:cytology; D000077338:Latanoprost; D050356:Lipid Metabolism; D008055:Lipids / Q000494:pharmacology; D051379:Mice; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology; D011461:Prostaglandins F, Synthetic / Q000737:chemistry / Q000494:pharmacology*; D011465:Prostaglandins, Synthetic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000145:classification / Q000187:drug effects* / Q000502:physiology*; D018078:Receptors, Prostaglandin E / Q000187:drug effects; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D014129:Trabecular Meshwork / Q000166:cytology / Q000187:drug effects; D000069557:Travoprost
chemical_list: D000577:Amides; D008055:Lipids; C545635:PTGER1 protein, human; C545647:PTGER3 protein, human; D011355:Prodrugs; D011453:Prostaglandins; D011461:Prostaglandins F, Synthetic; D011465:Prostaglandins, Synthetic; C545636:Ptger1 protein, mouse; C545637:Ptger1 protein, rat; C545648:Ptger3 protein, mouse; C545649:Ptger3 protein, rat; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; C091523:S 1033; C034671:prostaglandin F2alpha receptor; D003008:Cloprostenol; C072630:isopropyl unoprostone; D000077338:Latanoprost; D015237:Dinoprost; D000069580:Bimatoprost; D000069557:Travoprost