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Papers of the Week


Papers: 12 Oct 2024 - 18 Oct 2024


2024 Oct 10


ACS Med Chem Lett


39411536


15


10

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

Authors

Zadina JE, Szabo LZ, Al-Obeidi F, Zhang X, Ferreira Nakatani L, Ogbu C, Heien ML, Falk T, Bartlett MJ, Polt R

Abstract

Opioids acting at the mu opioid receptor (MOR) remain the most effective treatment for moderate to severe pain, but their use is limited by serious side effects. We have shown that a cyclized analog of endomorphin-1 provided pain relief comparable to that of morphine with reduction or absence of several side effects, including abuse liability. Glycosylation can promote penetration of cellular barriers. Here we developed cyclic glycopeptide endomorphin (glycoEM) analogs as drug candidates for potent and long-lasting analgesia. The analogs were assessed in receptor binding and functional assays and for blood-brain barrier penetration by microdialysis and MS. Two of the analogs showed MOR selectivity and more potent and longer lasting antinociception than morphine in male and female mice. Comparable antinociception occurred at A2 doses 5-fold lower (20-fold on a molar basis) than morphine doses. The results support further study of the glycoEMs for clinical application.