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Irreversible and noncompetitive mu opioid receptor agonists
Author(s) -
Stahl Edward,
Schmid Cullen L.,
AcevedoCanabal Agnes,
Read Cai,
Grim Travis,
Kennedy Nicole M.,
Bannister Thomas D.,
Bohn Laura M.
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r1962
Subject(s) - functional selectivity , antagonist , agonist , chemistry , g protein coupled receptor , g protein , receptor , intrinsic activity , pharmacology , opioid receptor , μ opioid receptor , ligand (biochemistry) , signal transduction , opioid , microbiology and biotechnology , biology , biochemistry
The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity or biased agonism. The presentation of ligand bias reflects selectivity between active states of the receptor which may result in the display of preferential engagement with one signaling pathway over another. In this study, we provide evidence that the G protein‐biased MOR agonists, SR‐17018 and SR‐14968 stabilize the mu opioid receptor in a wash‐resistant, yet antagonist‐reversible, G protein signaling state. Furthermore, we demonstrate that these structurally related biased agonists, are noncompetitive for radiolabeled MOR antagonist binding and while they stimulate G protein signaling in mouse brain, partial agonists of this class do not compete with full agonist activation. Importantly, opioid antagonists can readily reverse their effects in vivo. Given that chronic treatment with SR‐17018 does not lead to tolerance in several mouse pain models, this feature may be desirable for the development of long lasting opioid analgesics that remain sensitive to antagonist reversal of respiratory suppression.