Title |
Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species
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Published in |
Science Signaling, December 2017
|
DOI | 10.1126/scisignal.aan3398 |
Pubmed ID | |
Authors |
Markus Muttenthaler, Åsa Andersson, Irina Vetter, Rohit Menon, Marta Busnelli, Lotten Ragnarsson, Christian Bergmayr, Sarah Arrowsmith, Jennifer R Deuis, Han Sheng Chiu, Nathan J Palpant, Margaret O'Brien, Terry J Smith, Susan Wray, Inga D Neumann, Christian W Gruber, Richard J Lewis, Paul F Alewood |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 6 | 22% |
United Kingdom | 3 | 11% |
India | 1 | 4% |
Brazil | 1 | 4% |
Mexico | 1 | 4% |
Austria | 1 | 4% |
Italy | 1 | 4% |
France | 1 | 4% |
Turkey | 1 | 4% |
Other | 0 | 0% |
Unknown | 11 | 41% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 23 | 85% |
Scientists | 3 | 11% |
Practitioners (doctors, other healthcare professionals) | 1 | 4% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 57 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Master | 10 | 18% |
Researcher | 8 | 14% |
Student > Bachelor | 8 | 14% |
Student > Ph. D. Student | 7 | 12% |
Other | 2 | 4% |
Other | 11 | 19% |
Unknown | 11 | 19% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 7 | 12% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 11% |
Chemistry | 6 | 11% |
Agricultural and Biological Sciences | 5 | 9% |
Medicine and Dentistry | 5 | 9% |
Other | 12 | 21% |
Unknown | 16 | 28% |