Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species

Sci Signal. 2017 Dec 5;10(508):eaan3398. doi: 10.1126/scisignal.aan3398.


Oxytocin and vasopressin mediate various physiological functions that are important for osmoregulation, reproduction, cardiovascular function, social behavior, memory, and learning through four G protein-coupled receptors that are also implicated in high-profile disorders. Targeting these receptors is challenging because of the difficulty in obtaining ligands that retain selectivity across rodents and humans for translational studies. We identified a selective and more stable oxytocin receptor (OTR) agonist by subtly modifying the pharmacophore framework of human oxytocin and vasopressin. [Se-Se]-oxytocin-OH displayed similar potency to oxytocin but improved selectivity for OTR, an effect that was retained in mice. Centrally infused [Se-Se]-oxytocin-OH potently reversed social fear in mice, confirming that this action was mediated by OTR and not by V1a or V1b vasopressin receptors. In addition, [Se-Se]-oxytocin-OH produced a more regular contraction pattern than did oxytocin in a preclinical labor induction and augmentation model using myometrial strips from cesarean sections. [Se-Se]-oxytocin-OH had no activity in human cardiomyocytes, indicating a potentially improved safety profile and therapeutic window compared to those of clinically used oxytocin. In conclusion, [Se-Se]-oxytocin-OH is a novel probe for validating OTR as a therapeutic target in various biological systems and is a promising new lead for therapeutic development. Our medicinal chemistry approach may also be applicable to other peptidergic signaling systems with similar selectivity issues.

MeSH terms

  • Animals
  • Anxiety / drug therapy*
  • COS Cells
  • Chemistry, Pharmaceutical
  • Chlorocebus aethiops
  • Conditioning, Psychological / drug effects
  • Female
  • HEK293 Cells
  • Humans
  • Infusions, Intraventricular
  • Ligands
  • Male
  • Mice
  • Rats
  • Receptors, Oxytocin / agonists*


  • Ligands
  • Receptors, Oxytocin