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.

The significant pharmacological activity of 2,3-benzodiazepine-4-ones led to an increased interest in this compound family. However, the literature of the closely related 2,3,4-benzothiadiazepine 2,2-dioxides is rather scarce. Earlier we elaborated a synthesis of 5-aryl congeners variously substituted at the aromatic ring. In the present study, a new synthetic route was investigated via highly versatile intermediates, to extend the reaction to a wider aromatic substitution pattern and to the preparation of 5-alkyl and 5-H derivatives. The essence of this approach is, starting from benzaldehyde acetals, acetophenone and benzophenone ketals, to synthesize ortho-formyl- and ortho-acyl-arylmethanesulfonyl chlorides, which are suitable precursors of the target compounds. The synthesis was implemented as follows: ortho-lithiation of the corresponding acetals and ketals and subsequent treatment with paraformaldehyde, or alternatively in two steps, with DMF or ethyl formate, followed by reduction with NaBH4, led to the corresponding hydroxymethyl derivatives. Reaction of these latter with methanesulfonyl chloride gave mesylates that were used to S-alkylate thiourea to afford S-alkylisothiouronium salts. The final steps of the synthesis were carried out in a telescoped reaction. Treatment of the S-alkylisothiouronium salts with N-chlorosuccinimide resulted in the corresponding arylmethanesulfonyl chlorides. Subsequent reaction with hydrazine hydrate followed by an acidic treatment gave 2,3,4-benzothiadiazepine 2,2-dioxides.