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submitted on 22.07.2020 and posted on 23.07.2020by Krishna Sharma, Robert Cassell, HongYu Su, Arryn Blaine, Benjamin Cummins, Kendall Mores, David Johnson, Richard van Rijn, Ryan Altman
Opioid receptors can trigger two distinct pathways (G protein coupling and arrestin recruitment) that differentially regulate a host of desired and undesired pharmacological effects. Increasingly, “biased” opioids that selectively activate one pathway over the other are being developed to treat disorders in which µ- and κ-opioids receptors are involved, though the development of biased δ-opioid receptor agonists has remained rather quiescent. Herein, we identify the C-terminus of Tyr-ψ[(Z)CF=CH]-Gly-Leu-enkephalin as a key site to regulate bias of both δ- and µ-opioid receptor agonists. Using in vitro assays, substitution of the Leu5 carboxylate reduced β-arrestin recruitment through both the δ- and µ-opioid receptors in a predictable structure-dependent fashion, while retaining affinity and cAMP potency comparable to the C-terminal carboxylate. These substitutions should enable discovery of a range of tool compounds for exploring δ-opioid receptor pharmacology and toxicology, which will enable reevaluation of this target within the context of biased signaling.