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Research ArticleENDOCRINE AND REPRODUCTIVE

Pharmacology of (2S,4Z)-N-[(2S)-2-Hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a New Potent and Selective Nonpeptide Antagonist of the Oxytocin Receptor

Rocco Cirillo, Enrico Gillio Tos, Matthias K. Schwarz, Anna Quattropani, Alexander Scheer, Marc Missotten, Jerôme Dorbais, Anthony Nichols, Francesco Borrelli, Claudio Giachetti, Lucia Golzio, Paolo Marinelli, Russell J. Thomas, Claude Chevillard, Florence Laurent, Karine Portet, Claude Barberis and André Chollet
Journal of Pharmacology and Experimental Therapeutics July 2003, 306 (1) 253-261; DOI: https://doi.org/10.1124/jpet.103.049395
Rocco Cirillo
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Enrico Gillio Tos
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Matthias K. Schwarz
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Anna Quattropani
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Alexander Scheer
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Marc Missotten
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Jerôme Dorbais
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Anthony Nichols
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Francesco Borrelli
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Claudio Giachetti
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Lucia Golzio
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Paolo Marinelli
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Russell J. Thomas
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Claude Chevillard
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Florence Laurent
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Karine Portet
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Claude Barberis
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André Chollet
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Abstract

We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (compound 1). We report the biochemical, pharmacological, and pharmacokinetic characterization in vitro and in vivo of this compound. Compound 1 competitively inhibits binding of [3H]oxytocin and the peptide antagonist 125I-ornithine vasotocin analog to human and rat oxytocin receptor expressed in human embryonic kidney 293-EBNA or Chinese hamster ovary cells with nanomolar potency. Selectivity against vasopressin receptor subtypes is >6-fold for V1a and >350-fold for V2 and V1b. Compound 1 inhibits oxytocin-evoked intracellular Ca2+ mobilization (IC50 = 8 nM). Compound 1 has no intrinsic agonist activity at the oxytocin receptor. Oxytocininduced contraction of isolated rat uterine strips is blocked by compound 1 (pA2 = 7.82). In anesthetized nonpregnant rats, single administration of compound 1 by i.v. or oral routes causes dose-dependent inhibition of contractions elicited by repeated injections of oxytocin with ED50 = 3.5 mg/kg i.v. and 89 mg/kg p.o., respectively. Compound 1 significantly inhibits spontaneous uterine contractions in pregnant rats near term when administered intravenously or orally. We conclude that compound 1 is a potent, selective, and orally active nonpeptide oxytocin receptor antagonist, which is a suitable candidate for evaluation as a potential tocolytic agent for the management of preterm labor.

Footnotes

  • DOI: 10.1124/jpet.103.049395.

  • ABBREVIATIONS: OT, oxytocin; OT-R, oxytocin receptor; OVTA, ornithine vasotocin analog; PGF2α, prostaglandin F2α; CHO, Chinese hamster ovary; HEK, human embryonic kidney; PBS, phosphate-buffered saline; AVP, arginine vasopressin; AUC, area under the curve; SD, Sprague-Dawley; FLIPR, fluorescence imaging plate reader; PE, polyethylene; ANOVA, analysis of variance.

    • Received January 22, 2003.
    • Accepted March 13, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 1
1 Jul 2003
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Pharmacology of (2S,4Z)-N-[(2S)-2-Hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a New Potent and Selective Nonpeptide Antagonist of the Oxytocin Receptor
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Research ArticleENDOCRINE AND REPRODUCTIVE

Pharmacology of (2S,4Z)-N-[(2S)-2-Hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a New Potent and Selective Nonpeptide Antagonist of the Oxytocin Receptor

Rocco Cirillo, Enrico Gillio Tos, Matthias K. Schwarz, Anna Quattropani, Alexander Scheer, Marc Missotten, Jerôme Dorbais, Anthony Nichols, Francesco Borrelli, Claudio Giachetti, Lucia Golzio, Paolo Marinelli, Russell J. Thomas, Claude Chevillard, Florence Laurent, Karine Portet, Claude Barberis and André Chollet
Journal of Pharmacology and Experimental Therapeutics July 1, 2003, 306 (1) 253-261; DOI: https://doi.org/10.1124/jpet.103.049395

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Research ArticleENDOCRINE AND REPRODUCTIVE

Pharmacology of (2S,4Z)-N-[(2S)-2-Hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a New Potent and Selective Nonpeptide Antagonist of the Oxytocin Receptor

Rocco Cirillo, Enrico Gillio Tos, Matthias K. Schwarz, Anna Quattropani, Alexander Scheer, Marc Missotten, Jerôme Dorbais, Anthony Nichols, Francesco Borrelli, Claudio Giachetti, Lucia Golzio, Paolo Marinelli, Russell J. Thomas, Claude Chevillard, Florence Laurent, Karine Portet, Claude Barberis and André Chollet
Journal of Pharmacology and Experimental Therapeutics July 1, 2003, 306 (1) 253-261; DOI: https://doi.org/10.1124/jpet.103.049395
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