Oxytocin antagonists with changes in the Asn⁵ position shed light on hormone‐oxytocin receptor interactions

Since oxytocin agonists and antagonists have different structure‐activity relationships, we have investigated the stereostructural and stereoelectronic requirements of the Asn⁵ residue in oxytocin antagonists by the synthesis of four analogues of the potent, prolonged acting oxytocin antagonist [Pen¹,d‐Phe²,Thr⁴,Orn⁸]‐oxytocin (I) in which Asn⁵ was replaced respectively with Thr (II), Leu⁵ (III), Asp⁵ (IV) and Tyr⁵ (V). These analogues had pA₂ values in the antioxytocic in vitro rat uterine assay of 7.23 (I), 7.16 (II), 6.67 (III), 7.21 (IV), and 6.76 (IV), respectively. All were also found to be weakly potent in the in vivo anti‐vasopressor assay in the rat. These studies demonstrate very different structural and stereoelectronic requirements for oxytocin agonists and antagonists when they interact with the oxytocin uterine receptor.