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, N^CyPr)

SUBMITTER: Sharma KK 

PROVIDER: S-EPMC8597420 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature