Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs

Rhiannon Beard, Andy Stucki, Muriel Schmitt, Gabrielle Py, Christophe Grundschober, Antony Gee, Edward Tate

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)
162 Downloads (Pure)


Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta) gave highest affinity (50 nM Ki), selectivity (34-fold), and agonist potency (34 nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC50) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study.
Original languageEnglish
JournalBioorganic and Medicinal Chemistry
Early online date12 Mar 2018
Publication statusE-pub ahead of print - 12 Mar 2018


  • Oxytocin
  • Disulfide bridging
  • Cyclic peptides
  • Peptide-based drugs
  • Increased stability


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