title: Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat.
abstract: Spontaneous and induced uterine contractions in the rat were found to be inhibited by a novel and selective oxytocin receptor antagonist GSK221149A (3R,6R)-3-Indan-2-yl-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione. GSK221149A displayed nanomolar affinity (K(i) = 0.65 nM) for human recombinant oxytocin receptors with >1,400-fold selectivity over human V1a, V1b, and V2 receptors. GSK221149A had similar affinity (K(i) = 4.1 nM) and selectivity for native oxytocin receptors from rat and produced a functional, competitive block of oxytocin-induced contractions in isolated rat myometrial strips with a pA(2) value of 8.18. Intravenous administration of GSK221149A produced a dose-dependent decrease in oxytocin-induced uterine contractions in anesthetized rats with an ID(50) = 0.27 +/- 0.60 mg/kg (corresponding plasma concentrations were 88 ng/ml). Oral administration of GSK221149A (5 mg/kg) was effective in inhibiting oxytocin-induced uterine contractions after single and multiple (4-day) dosing. Spontaneous uterine contractions in late-term pregnant rats (19-21 days gestation) were significantly reduced by intravenous administration of 0.3 mg/kg of GSK221149A. These results provide further evidence that selective oxytocin receptor antagonism may offer an effective treatment for preterm labor.
authors: Department of Urogenital Biology, GlaxoSmithKline Research and Development, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors: Gerald P
authors: GP
authors: McCafferty
authors: Mark A
authors: MA
authors: Pullen
authors: Charlene
authors: C
authors: Wu
authors: Richard M
authors: RM
authors: Edwards
authors: Michael J
authors: MJ
authors: Allen
authors: Patrick M
authors: PM
authors: Woollard
authors: Alan D
authors: AD
authors: Borthwick
authors: John
authors: J
authors: Liddle
authors: Deirdre M B
authors: DM
authors: Hickey
authors: David P
authors: DP
authors: Brooks
authors: Timothy D
authors: TD
authors: Westfall
mesh_terms: D000758:Anesthesia; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D010121:Oxytocin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D010298:Parity; D010879:Piperazines / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors*; D017483:Receptors, Vasopressin / Q000187:drug effects; D014162:Transfection; D014590:Uterine Contraction / Q000502:physiology*; D014667:Vasopressins / Q000494:pharmacology
chemical_list: C522194:GSK221149A; D010879:Piperazines; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D014667:Vasopressins; D010121:Oxytocin