Acute and chronic pain is often treated with opioids despite the negative side effects of constipation, physical dependence, respiratory depression, and overdose. The misuse of opioid analgesics has given rise to the opioid crisis/epidemic, and alternate nonaddictive analgesics are urgently needed. Oxytocin, a pituitary hormone, is an alternative to the small molecule treatments available and has been used as an analgesic as well as for the treatment and prevention of opioid use disorder (OUD). Clinical implementation is limited by its poor pharmacokinetic profile, a result of the labile disulfide bond between two cysteine residues in the native sequence. Stable brain penetrant oxytocin analogues have been synthesized by replacement of the disulfide bond with a stable lactam and glycosidation of the C-terminus. These analogues show exquisite selectivity for the oxytocin receptor and potent in vivo antinociception in mice following peripheral (i.v.) administration, supporting further study of their clinical potential.

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.