Résumé
Preterm birth is the single largest cause of neonatal morbidity and death [1]. Oxytocin antagonists have been extensively studied as possible therapeutic agents for the treatment of premature labor [2]. The oxytocin antagonist (OTA) atosiban ([1-deamino, D-Tyr(Et)2,Thr4]OVT) has been shown to be an effective tocolytic for the treatment of pre-term labor [3]. Atosiban is in fact the only OTA (peptide or nonpetide) approved for clinical use (in Europe) [4]. Atosiban is however far from an ideal OTA. It is highly nonselective for OT receptors versus vasopressin (VP) V1a receptors. In the rat it is only 8 times more potent as an OTA than as a V1a antagonist in vivo [5]. However, in humans its affinity for Vla receptors is 100 times greater than for OT receptors [6], It is thus a strikingly more potent Vla antagonist than an OTA in humans. We have shown that Vla antagonism is an undesirable side effect in OTAs [7]. Here we report the synthesis and some pharmacological properties of the following six L-Thi2/D-Thi2 (where Thi = β-thienylalanine) OTAs: 1 d(CH2)5[Thi2,Thi4,Tyr-NH29]OVT, 2 d(CH2)5[D-Thi2, Thi4,Tyr-NH29]OVT, 3d(CH2)5[Thi4,Thr4,Eda9]OVT, 4 d(CH2)5[D-Thi2,Th4,Eda9]OVT, 5 d(CH2)5[Thi2, Thr4,Eda9⇽Tyr10]OVT, 6 d(CH2)5[D-Thi2,Th4,Eda9⇽Tyr10]OVT; all of which are more selective than atosiban in rat bioassays and in human receptor assays.