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

Muttenthaler, Markus
Andersson, Åsa
Vetter, Irina
Menon, Rohit
Busnelli, Marta
Ragnarsson, Lotten
Bergmayr, Christian
Arrowsmith, Sarah
Deuis, Jennifer R.
Chiu, Han Sheng
... show 8 more
Muttenthaler, Markus; Andersson, Åsa; Vetter, Irina; Menon, Rohit; Busnelli, Marta; Ragnarsson, Lotten; Bergmayr, Christian; Arrowsmith, Sarah; Deuis, Jennifer R. Chiu, Han Sheng; Palpant, Nathan J.; O’Brien, Margaret; Smith, Terry J.; Wray, Susan; Neumann, Inga D.; Gruber, Christian W.; Lewis, Richard J.; Alewood, Paul F. (2017). Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species. Science Signaling 10 (508),
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.
American Association for the Advancement of Science (AAAS)
Publisher DOI
Attribution-NonCommercial-NoDerivs 3.0 Ireland