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

Cell | Nov 16, 2017

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.

Pubmed ID: 29149605 RIS Download

Mesh terms: Analgesics, Opioid | Animals | Fentanyl | GTP-Binding Proteins | Mice | Morphine | Receptors, Opioid, mu | Respiratory System | Signal Transduction | beta-Arrestins