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Cell. 2017 Nov 16;171(5):1165-1175.e13. doi: 10.1016/j.cell.2017.10.035.

Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics.

Author information

1
Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
2
Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
3
Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
4
Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: lbohn@scripps.edu.

Abstract

Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias. We find that βarrestin-biased compounds, such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression.

KEYWORDS:

G protein-coupled receptor (GPCR); biased agonism; fentanyl; functional selectivity; morphine; mu opioid receptor; pain; respiration; side effects; βarrestin

PMID:
29149605
PMCID:
PMC5731250
DOI:
10.1016/j.cell.2017.10.035
[Indexed for MEDLINE]
Free PMC Article

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