| First Author | Schmid CL | Year | 2017 |
| Journal | Cell | Volume | 171 |
| Issue | 5 | Pages | 1165-1175.e13 |
| PubMed ID | 29149605 | Mgi Jnum | J:249987 |
| Mgi Id | MGI:6101093 | Doi | 10.1016/j.cell.2017.10.035 |
| Citation | Schmid CL, et al. (2017) Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics. Cell 171(5):1165-1175.e13 |
| abstractText | 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 betaarrestin 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 betaarrestin-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. |
