Structure-Based Design of Glycosylated Oxytocin Analogues with Improved Selectivity and Antinociceptive Activity.
Lajos Z SzabóParthasaradhireddy TanguturiHannah J GoodmanSára SprőberChenxi LiuFahad Al-ObeidiMitchell J BartlettTorsten FalkVlad K KumirovM Leandro HeienJohn M StreicherRobin PoltPublished in: ACS medicinal chemistry letters (2023)
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.
Keyphrases
- chronic pain
- pain management
- small molecule
- molecular docking
- anti inflammatory
- public health
- healthcare
- depressive symptoms
- liver failure
- mental health
- metabolic syndrome
- spinal cord injury
- resting state
- intensive care unit
- multiple sclerosis
- blood brain barrier
- neuropathic pain
- drug induced
- quality improvement
- newly diagnosed
- climate change
- combination therapy
- functional connectivity
- living cells
- single molecule
- molecular dynamics simulations
- acute respiratory distress syndrome