Synthesis and biological activity of oxytocin analogues containing conformationally-restricted residues in position 7

We report the solid-phase synthesis and some pharmacological properties of twenty oxytocin (OT) analogues. Basic modifications at position 7 (introduction of α-aminoisobutyric acid [Aib], l- or d-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [l/d-Tic], l-α-t-butylglycine [Gly(But)] and pipecolic acid [Pip]) were combined with d-Tyr(Et)2, l/d-(pEt)Phe2, d-Tic2, and Mpa1 modifications and their various combinations in a total of 14 analogues. Additionally, two analogues having one more modification in position 3, i.e. Gly(But), and three analogues having glycine in position 9 substituted by d-Tic or Aib, were prepared. The analogues were tested for rat uterotonic activity in vitro, in the rat pressor assay and for binding affinity to human OT receptor. The analogue having the highest antioxytocic activity was [Mpa1, d-Tyr(Et)2, d-Tic7, Aib9]OT having pA2 = 8.31 ± 0.19; this analogue was also selective.

Graphical abstractTwenty oxytocin analogues were synthesized and their biological activity was studied. Three of them are promising lead for the synthesis of potent and selective oxytocin antagonistsFigure optionsDownload full-size imageDownload as PowerPoint slide