SR17018: A G-Protein Biased Mu-Opioid Receptor Agonist
SR17018 is a G-protein biased mu-opioid receptor (MOR) agonist that produces effective analgesia without causing significant respiratory depression, demonstrating a superior safety profile compared to traditional opioids. 1
Pharmacological Profile
- SR17018 functions as a mu-opioid receptor agonist with strong bias toward G-protein signaling pathways while minimizing β-arrestin2 recruitment, which is believed to be responsible for many opioid side effects 1, 2
- The compound achieves its bias against β-arrestin2 recruitment through a unique mechanism involving interactions with mu-opioid receptors outside the traditional orthosteric agonist binding site 2
- SR17018 exhibits an atypical mu-opioid receptor phosphorylation and dephosphorylation pattern that differs significantly from other known biased, partial, or full MOR agonists 3
Therapeutic Effects
- SR17018 produces dose-dependent and fully efficacious antinociception across multiple pain modalities, comparable to traditional opioids like fentanyl and oxycodone 1
- Unlike conventional opioids, SR17018 does not produce respiratory depression at doses that provide effective pain relief, offering a significantly improved safety profile 1
- The compound has demonstrated the ability to reverse morphine tolerance and prevent withdrawal symptoms through its unique mechanism of action 3
Safety Profile and Advantages
- SR17018 shows reduced abuse potential compared to conventional opioids like fentanyl and oxycodone, though it still functions as a reinforcer in animal models 1
- The compound does not cause respiratory depression at doses exceeding those required for analgesia, addressing one of the most dangerous side effects of traditional opioids 1
- SR17018's unique pharmacological profile suggests it could provide effective pain management with fewer adverse effects than currently available opioid medications 1, 2, 3
Molecular Characteristics
- SR17018 exhibits distinctive binding properties at the mu-opioid receptor, with naloxone and cyprodime showing non-competitive antagonism patterns against it in β-arrestin2 recruitment assays 2
- Unlike other opioids, SR17018 only negligibly diminishes β-arrestin2 recruitment stimulated by DAMGO, further supporting its atypical mechanism of action 2
- The compound induces a persistent mu-opioid receptor phosphorylation that remains for hours after exposure, unlike the rapidly reversible phosphorylation seen with full agonists like DAMGO 3
Research Status and Future Directions
- SR17018 is currently being investigated as a foundational molecule for the development of safer analgesics with improved therapeutic windows 1
- The compound's unique pharmacological properties make it a valuable research tool for understanding the relationship between opioid receptor signaling pathways and their associated therapeutic and adverse effects 2, 3
- Further studies are needed to fully characterize SR17018's clinical potential and to develop derivatives with optimized properties for potential therapeutic use 1