Modulating β-arrestin 2 recruitment at the δ- and μ-opioid receptors using peptidomimetic ligands

Abstract

μ-Opioid receptor agonists provide potent and effective acute analgesia; however, their therapeutic window narrows considerably upon repeated administration, such as required for treating chronic pain. In contrast, bifunctional μ/δ opioid agonists, such as the endogenous enkephalins, have potential for treating both acute and chronic pain. However, enkephalins recruit β-arrestins, which correlate with certain adverse effects at μ- and δ-opioid receptors. Herein, we identify the C-terminus of Tyr-ψ[(Z)CF[double bond, length as m-dash]CH]-Gly-Leu-enkephalin, a stable enkephalin derivative, as a key site to regulate bias of both δ- and μ-opioid receptors. Using in vitro assays, substitution of the Leu5 carboxylate with amides (NHEt, NMe2, NCyPr) reduced β-arrestin recruitment efficacy through both the δ-opioid and μ-opioid, while retaining affinity and cAMP potency. For this series, computational studies suggest key ligand–receptor interactions that might influence bias. These findings should enable the discovery of a range of tool compounds with previously unexplored biased μ/δ opioid agonist pharmacological profiles.

Graphical abstract: Modulating β-arrestin 2 recruitment at the δ- and μ-opioid receptors using peptidomimetic ligands

Supplementary files

Article information

Article type
Research Article
Submitted
25 Jan 2021
Accepted
11 Aug 2021
First published
16 Aug 2021

RSC Med. Chem., 2021, Advance Article

Modulating β-arrestin 2 recruitment at the δ- and μ-opioid receptors using peptidomimetic ligands

K. K. Sharma, R. J. Cassell, Y. J. Meqbil, H. Su, A. T. Blaine, B. R. Cummins, K. L. Mores, D. K. Johnson, R. M. van Rijn and R. A. Altman, RSC Med. Chem., 2021, Advance Article , DOI: 10.1039/D1MD00025J

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