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

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.

Oxytocin structure and function in New World monkeys: from pharmacology to behavior

“…However, our observations that naturally occurring modifications in the OT/OTR system among NWMs lead to significant functional consequences provides an intriguing ‘natural experiment’ to explore OT under a new lens. Our approach should be viewed as complementary to efforts that explore laboratory-induced changes in the OT molecule as a means to discover super potent and efficacious synthetic ligands as potential candidates for clinically relevant endpoints (e.g., Busnelli et al 2016; Muttenthaler et al 2017). Overall, these findings from OT pharmacology to OT-induced behavioral changes clearly demonstrate that OT/OTR structural modifications in NWM that arise from natural selection can orchestrate important changes in OT-mediated physiological and behavioral outcomes.…”

Binding Characteristics of Two Oxytocin Variants and Vasopressin at Oxytocin Receptors from Four Primate Species with Different Social Behavior Patterns

“…Because of its ability to modulate a wide variety of social behaviors (Lee et al, 2009), OT is currently being evaluated for its clinical use in disorders with a social component, such as autism spectrum disorder and schizophrenia (Bakermans-Kranenburg and van Ijzendoorn, 2013;Feifel et al, 2016;DeMayo et al, 2017;Parker et al, 2017). Considerable effort has been invested in engineering OT analogs and formulations for potential therapeutic use and to extend understanding of OT actions, particularly central nervous system and behavioral effects (Manning et al, 2012;Busnelli et al, 2013;Muttenthaler et al, 2017). Although these efforts with novel synthetic analogs have been reasonably successful, naturally occurring variants of the OT peptide could provide an alternate route to novel agents and therapies (Gruber et al, 2012).…”

“…The nonapeptide family of hormone ligands is ancient and is present in nearly all animal lineages (Beets et al, 2013;Lockard et al, 2017). OT-like ligands generally vary at the third, fourth, or eighth amino acid position (Gruber et al, 2012), and the amino acid at the eighth position strongly affects the activity of the peptide on its target organs (Sawyer and Manning, 1973;Manning et al, 2012;Muttenthaler et al, 2017). OT and the closely related nonapeptide arginine vasopressin (AVP) differ at amino acid positions 3 and 8 and have vastly different roles in mammalian physiology, even though the affinity of OT for OTRs is only 2-fold greater than the affinity of AVP for OTRs (Manning et al, 2012).…”

The oxytocin receptor signalling system and breast cancer: a critical review

“…To improve the translational perspectives, in vivo studies targeting OTR in human breast cancer xenograft models are required. OT, while important as the endogenous ligand, might also not be the ideal ligand for therapeutic development, considering that it also activates the three to OTR closely related vasopressin receptors (V 1a R, V 1b R, V 2 R, discussed in sections below) [103] and its short systemic half-life [104]. More systematic studies and OTR drug lead development is, in our opinion, necessary before moving towards clinical translation.…”

“…3) [4,8,133]. The homology of the binding sites of the OTR and VPRs is~80%, thus leading to significant cross-talk [103,134,135]. OT can not only activate OTR, but also the VPRs, while VP can also activate OTR.…”