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.

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.

• Authors: Rocco Cirillo, Enrico Gillio Tos, Matthias K Schwarz, Anna Quattropani, Alexander Scheer, Marc Missotten, Jerome Dorbais, Anthony Nichols, Francesco Borrelli, Claudio Giachetti, Lucia Golzio, Paolo Marinelli, Russell J Thomas, Claude Chevillard, Florence Laurent, Karine Portet, Claude Barberis, Andre Chollet
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 306 Issue 1 Pg. 253-61 (Jul 2003) ISSN: 0022-3565 [Print] United States
• PMID: 12660315 (Publication Type: Journal Article)

Chemical References

• Imines
• N-(2-hydroxy-2-phenylethyl)-4-(methoxyimino)-1-((2'-methyl(1,1'-biphenyl)-4-yl)carbonyl)-2-pyrrolidinecarboxamide
• Pyrrolidines
• Receptors, Oxytocin
• Receptors, Vasopressin
• Oxytocin
• Dinoprost

Topics

• Anesthesia
• Animals
• CHO Cells
• Cells, Cultured
• Cricetinae
• Dinoprost (pharmacology)
• Dose-Response Relationship, Drug
• Female
• Humans
• Imines (pharmacology)
• Oxytocin (pharmacology)
• Pregnancy
• Pyrrolidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Receptors, Oxytocin (antagonists & inhibitors)
• Receptors, Vasopressin (metabolism)
• Uterine Contraction (drug effects)