Antagonists for the human oxytocin receptor: an in vitro study.

The oxytocin antagonist [Mpa1, D-Tyr(Et)2, Thr4, Orn8]-oxytocin has been successfully used for treating premature labour. The interactions of this antagonist with neurohypophysialhormone receptors in the human myometrium were investigated. Competition curves among [3H]oxytocin, [3H]arginine vasopressin, [3H][1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)2-(O-methyl)-tyrosine, 8-arginine] vasopressin, the corresponding unlabelled peptides and a series of oxytocin antagonists including [Mpa1,D-Tyr(Et)2,Thr4,Orn8]-oxytocin were constructed from results taken from the myometrium of pregnant women and rabbits, and were analysed simultaneously using the computer program LIGAND. The biological activity of [Mpa1,D-Tyr(Et)2,Thr4,Orn8]-oxytocin in the human uterus was investigated by studying its effect on oxytocin-induced intracellular Ca2+ mobilization in human myometrial cells in culture that were expressing high concentrations of oxytocin receptors. The results indicate that [Mpa1,D-Tyr(Et)2,Thr4,Orn8]-oxytocin and related antagonists are selective for the oxytocin receptor in the myometrium of pregnant rabbits but not of pregnant women. In women, they bind with high affinity to the V1 vasopressin receptor. In myometrial cells [Mpa1,D-Tyr(Et)2,Thr4,Orn8]- oxytocin inhibits the oxytocin-induced increase in intracellular Ca2+ concentration in a dose-dependent fashion, with an IC50 value of 5 nmol l-1. The uterine relaxant effect of this antagonist might result not only from the block of the oxytocin receptor, but also from interaction with the V1 vasopressin receptor.