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.
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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)
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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
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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)
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