期刊
SCIENCE SIGNALING
卷 10, 期 508, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aan3398
关键词
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资金
- National Health and Medical Research Council (NHMRC) Project [1063803, 1072113]
- Australian Research Council (ARC) Future Fellowship grant [FT130101215]
- NHMRC Fellowship
- European Union Seventh Framework Programme (FP7) under Marie Curie Actions grant from the Secretary of Universities [254897]
- Universities and Research of the Economy and Knowledge Department of the Government of Catalonia, from the ARC [DE150100784, 2013-BP-B-00109]
- European Research Council under the European Union's Horizon Research and Innovation Programme [714366]
- Vienna Science and Technology Fund (WWTF) [LS13-017]
- Harris-Wellbeing Preterm Birth Research Centre grant
- DFG [Ne 465/27-1]
- German Ministry of Education and Research (BMBF
- OptiMD) [01EE1401A]
- European Union Seventh Framework (FemNAT CD) [Health-F2-2013-602407]
- National Health and Medical Research Council of Australia [1063803, 1072113] Funding Source: NHMRC
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.
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