We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species.
- Authors
Muttenthaler, Markus; Andersson, Åsa; Vetter, Irina; Menon, Rohit; Busnelli, Marta; Ragnarsson, Lotten; Bergmayr, Christian; Arrowsmith, Sarah; Deuis, Jennifer R.; Han Sheng Chiu; Palpant, Nathan J.; O'Brien, Margaret; Smith, Terry J.; Wray, Susan; Neumann, Inga D.; Gruber, Christian W.; Lewis, Richard J.; Alewood, Paul F.
- Abstract
Oxytocin and vasopressin mediate various physiological functions that are important for osmoregulation, reproduction, cardiovascular function, social behavior,memory and learning through fourGprotein--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 wasmediated byOTR 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 newlead for therapeutic development. Ourmedicinal chemistry approachmay also be applicable to other peptidergic signaling systems with similar selectivity issues.
- Subjects
OXYTOCIN receptors; VASOPRESSIN; CANNABINOID receptors; GENE expression; NEUROPEPTIDES; PARAVENTRICULAR nucleus
- Publication
Science Signaling, 2017, Vol 10, Issue 508, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aan3398