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Am J Physiol Regul Integr Comp Physiol 293: R299-R305, 2007. First published March 29, 2007; doi:10.1152/ajpregu.00057.2007
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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat

Gerald P. McCafferty,1 Mark A. Pullen,1 Charlene Wu,1 Richard M. Edwards,1 Michael J. Allen,3 Patrick M. Woollard,2 Alan D. Borthwick,2 John Liddle,2 Deirdre M. B. Hickey,2 David P. Brooks,1 and Timothy D. Westfall1

1Departments of Urogenital Biology, 2Medicinal Chemistry and Drug Metabolism and Pharmacokinetics, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Research and Development, King of Prussia, Pennsylvania and Gunnels Wood Road, Stevenage, Herts, United Kingdom; and 3Department of Assay Development and Compound Profiling, GlaxoSmithKline, New Frontiers, Science Park, Harlow, Essex, United Kingdom

Submitted 25 January 2007 ; accepted in final form 21 March 2007

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 (Ki = 0.65 nM) for human recombinant oxytocin receptors with >1,400-fold selectivity over human V1a, V1b, and V2 receptors. GSK221149A had similar affinity (Ki = 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 pA2 value of 8.18. Intravenous administration of GSK221149A produced a dose-dependent decrease in oxytocin-induced uterine contractions in anesthetized rats with an ID50 = 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.

preterm labor; myometrium


Address for reprint requests and other correspondence: T. D. Westfall, 709 Swedeland Rd., Mail Code UW2521, King of Prussia, PA 19406, USA (e-mail: timothy.d.westfall{at}gsk.com)






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