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Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics

2017; Cell Press; Volume: 171; Issue: 5 Linguagem: Inglês

10.1016/j.cell.2017.10.035

1097-4172

Cullen L. Schmid, Nicole Kennedy, Nicolette C. Ross, Kimberly M. Lovell, Zhizhou Yue, Jenny Morgenweck, Michael D. Cameron, Thomas D. Bannister, Laura Bohn,

Pharmacological Receptor Mechanisms and Effects

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.