Structure-Based Design of Glycosylated Oxytocin Analogues with Improved Selectivity and Antinociceptive Activity

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Feb 16

PMID 36793431

Authors

Lajos Z Szabo

Parthasaradhireddy Tanguturi

Hannah J Goodman

Sara Sprober

Chenxi Liu

Fahad Al-Obeidi

Mitchell J Bartlett

Torsten Falk

Vlad K Kumirov

M Leandro Heien

John M Streicher

Robin Polt

Affiliations

Soon will be listed here.

Abstract

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 antinociception in mice following peripheral (i.v.) administration, supporting further study of their clinical potential.

Citing Articles

Cyclic Glycopeptide Analogs of Endomorphin-1 Provide Highly Effective Antinociception in Male and Female Mice.

Zadina J, Szabo L, Al-Obeidi F, Zhang X, Ferreira Nakatani L, Ogbu C ACS Med Chem Lett. 2024; 15(10):1731-1740.

PMID: 39411536 PMC: 11472388. DOI: 10.1021/acsmedchemlett.4c00315.

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