Molecules, Vol. 26, Pages 4509: SR-17018 Stimulates Atypical µ-Opioid Receptor Phosphorylation and Dephosphorylation

Molecules, Vol. 26, Pages 4509: SR-17018 Stimulates Atypical µ-Opioid Receptor Phosphorylation and Dephosphorylation Molecules doi: 10.3390/molecules26154509 Authors: Sebastian Fritzw.er Stefan Schulz Andrea Kliewer Opioid-associated overdoses and deaths due to respiratory depression are a major public health problem in the US and other Western countries. In the past decade, much research effort has been directed towards the development of G-protein-biased µ-opioid receptor (MOP) agonists as a possible means to circumvent this problem. The bias hypothesis proposes that G-protein signaling mediates analgesia, whereas ß-arrestin signaling mediates respiratory depression. SR-17018 was initially reported as a highly biased µ-opioid with an extremely wide therapeutic window. It was later shown that SR-17018 can also reverse morphine tolerance and prevent withdrawal via a hitherto unknown mechanism of action. Here, we examined the temporal dynamics of SR-17018-induced MOP phosphorylation and dephosphorylation. Exposure of MOP to saturating concentrations of SR-17018 for extended periods of time stimulated a MOP phosphorylation pattern that was indistinguishable from that induced by the full agonist DAMGO. Unlike DAMGO-induced MOP phosphorylation, which is reversible within minutes after agonist washout, SR-17018-induced MOP phosphorylation persisted for hours under otherwise identical conditions. Such delayed MOP dephosphorylation kinetics were also found for the pa...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research