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

Muttenthaler, Markus, Andersson, Asa, 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. and Alewood, Paul F. (2017) Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species. Science Signaling, 10 508: 1-13. doi:10.1126/scisignal.aan3398

Author Muttenthaler, Markus
Andersson, Asa
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.
Title Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species
Journal name Science Signaling   Check publisher's open access policy
ISSN 1945-0877
Publication date 2017-12-05
Year available 2017
Sub-type Article (original research)
DOI 10.1126/scisignal.aan3398
Open Access Status Not yet assessed
Volume 10
Issue 508
Start page 1
End page 13
Total pages 13
Place of publication Washington, DC United States
Publisher American Association for the Advancement of Science
Language eng
Subject 1303 Biochemistry
1312 Molecular Biology
1307 Cell Biology
Abstract 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.
Keyword Phase Peptide-Synthesis
Social Behaviors
Human Myometrium
Vasopressin Receptors
Human Cardiomyocytes
Antagonist Atosiban
Nonpeptide Agonists
Intranasal Oxytocin
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: School of Biomedical Sciences Publications
School of Pharmacy Publications
Institute for Molecular Bioscience - Publications
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Created: Sat, 16 Dec 2017, 23:01:45 EST