Bias factor and therapeutic window correlate to predict safer opioid analgesics
| Autor: | Cullen L. Schmid, Nicole M. Kennedy, Zhizhou Yue, Nicolette C. Ross, Jenny Morgenweck, Laura M. Bohn, Michael D. Cameron, Thomas D. Bannister, Kimberly M. Lovell |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Morphine G protein Oliceridine Biology Pharmacology Ligands General Biochemistry Genetics and Molecular Biology Article Fentanyl Analgesics Opioid 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology chemistry medicine Functional selectivity Animals μ-opioid receptor Receptor medicine.drug G protein-coupled receptor Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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