title: THG113: a novel selective FP antagonist that delays preterm labor.
abstract: PGF2alpha is an important smooth muscle contractile agent that exerts significant effects on myometrium and is implicated in labor. THG113 was recently identified as a PGF2alpha receptor (FP) antagonist. We characterized the specificity and selectivity of THG113, tested its effects on PGF2alpha-induced smooth muscle contraction, and assessed its efficacy in a model of endotoxin (LPS)-induced preterm labor. [125I]THG113 bound specifically to FP-expressing but not to native (not expressing FP) HEK293 cells. In FP-expressing HEK293 cells, THG113 markedly reduced PGF2alpha-elicited phosphoinositide hydrolysis (IC50 27 nM). Similarly, PGF2alpha-evoked microvascular (retinal) contraction was noncompetitively blocked (by > 90%) by THG113. In contrast, contraction to agonists of homologous prostanoid receptors EP1 and TP (17-phenyl-trinor PGE2 and U46619) was unaffected (< 1%) by high concentrations of THG113 (100 micromol/L); THG113 (100 micromol/L) also did not affect contraction to numerous other agents including platelet activating factor, endothelin, and angiotensin II. Force and duration of PGF2alpha-evoked contractions of myometrial strips of pig (non-pregnant, luteal phase) and mouse (immediately postpartum) were markedly reduced by THG113. In an endotoxin-induced preterm mouse model, lipopolysaccharide (50 microg intraperitioneal) injection at 16 days' gestation resulted in 100% delivery within 15 h; in contrast, 70% of those treated with THG113 (1 mg/day) delivered > 24 h later (at 18 days' gestation; term: 19 days). In addition, in mice injected with lipopolysaccharide and treated 6 h later with THG113 (0.1 mg bolus followed by 1 mg/day) 40% delivered > 48 h later. Fetuses of pregnant mice treated with THG113 were born alive, had higher birth weights (1.6 +/- 0.1 v 1.4 +/- 0.05 g), and appeared healthy. This study describes an effective and selective noncompetitive FP antagonist, THG113, which significantly delays preterm delivery; this provides the basis for future investigations for its use in tocolysis.
authors.affiliation: Department of Pediatrics, Research Center of Hôpital Ste. Justine, Montréal, Québec.
authors.forename: Krishna G
authors.initials: KG
authors.lastname: Peri
authors.forename: Christiane
authors.initials: C
authors.lastname: Quiniou
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.forename: Daniel
authors.initials: D
authors.lastname: Abran
authors.forename: Daya R
authors.initials: DR
authors.lastname: Varma
authors.forename: William D
authors.initials: WD
authors.lastname: Lubell
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D015237:Dinoprost / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007752:Obstetric Labor, Premature / Q000517:prevention & control*; D011247:Pregnancy; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000502:physiology; D013552:Swine; D015149:Tocolytic Agents / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D007295:Inositol Phosphates; D008070:Lipopolysaccharides; D011982:Receptors, Prostaglandin; D015149:Tocolytic Agents; D014662:Vasoconstrictor Agents; C034671:prostaglandin F2alpha receptor; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost