G protein signaling-biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists.

Autor:	Stahl EL; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458., Schmid CL; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458., Acevedo-Canabal A; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458., Read C; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458., Grim TW; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458., Kennedy NM; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458., Bannister TD; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458., Bohn LM; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458 lbohn@scripps.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Nov 30; Vol. 118 (48).
DOI:	10.1073/pnas.2102178118
Abstrakt:	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, and 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 mu opioid receptor (MOR) agonists SR-17018 and SR-14968 stabilize the MOR 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 brains, 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. Competing Interests: Competing interest statement: The Scripps Research Institute has filed for a patent on the SR compounds used in this study.
Databáze:	MEDLINE
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