Research ResourcePharmacology

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

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Sci. Signal.  05 Dec 2017:
Vol. 10, Issue 508, eaan3398
DOI: 10.1126/scisignal.aan3398

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A more selective oxytocin receptor agonist

Oxytocin is clinically used to induce labor, and there is interest in using this peptide to treat social disorders. However, oxytocin triggers adverse cardiovascular side effects because it activates the vasopressin receptor and the oxytocin receptor. Muttenthaler et al. generated ligands based on oxytocin with subtle modifications, yielding a lead compound that was more selective for the oxytocin receptor than for the vasopressin receptors. It reduced social fear in mice and induced contractile activity in human myometrial strips without affecting cultured cardiomyocytes. Given the cross-talk between oxytocin, vasopressin, and their receptors, this compound will also be helpful in identifying effects that are solely mediated by the oxytocin receptor.

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.

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