Structure-based design of glycosylated oxytocin analogues with improved selectivity and antinociceptive activity

Abstract Pain, both acute and chronic, is often treated with opioids despite severe negative side effects, such as physical dependence, respiratory depression and overdose. In the United States the misuse of opioid analgesics has given rise to the opioid crisis or opioid epidemic. As the frequency of overdoses increases, the need for alternative, non-addictive analgesics has become increasingly urgent. Oxytocin, a pituitary hormone, has shown robust evidence for analgesia and shows promise for treatment and prevention of opioid use disorder. Despite decades of research, clinical implementation is hindered by the poor pharmacokinetic profile of the native hormone oxytocin, which is cyclized by a labile disulfide bond. We addressed this by replacing the disulfide bond with a more stable lactam; additionally, we have glycosylated the cyclic peptides to yield brain penetrant oxytocin analogues. These analogues show exquisite selectivity for the oxytocin receptor and potent in vivo antinociception in mice following peripheral administration, suggesting further study toward clinical applications for pain treatment.