SR-17018 EU

SR-17018 is a next-generation opioid analgesic candidate known for its biased agonism at the μ-opioid receptor (MOR). Unlike traditional opioids like morphine or oxycodone, which activate both G protein and β-arrestin 2 pathways, SR-17018 selectively favors the G protein signaling pathway. This novel pharmacological bias has been associated with reduced side effects, particularly respiratory depression, tolerance, and dependence, making SR-17018 a promising compound in the field of pain management and neuropharmacology.

Mechanism of Action

SR-17018 exhibits G protein-biased agonism, meaning it preferentially stimulates intracellular G protein signaling over the β-arrestin 2 pathway. Research has shown that many adverse effects of opioids—such as sedation, constipation, and respiratory depression—are mediated by β-arrestin 2 recruitment. By avoiding this pathway, SR-17018 seeks to preserve analgesia while minimizing toxicity.

Key mechanisms include:

• High MOR selectivity

• Minimal β-arrestin recruitment

• Potent activation of Gαi/o signaling

• Reduced internalization of MOR, potentially limiting tolerance development

Pharmacokinetics

While human data are limited, preclinical studies in rodents demonstrate:

• High oral bioavailability

• Central nervous system (CNS) penetration

• Hepatic metabolism with CYP involvement

• Half-life of approximately 6–8 hours

These parameters support the feasibility of oral dosing, a major advantage over injectable or transdermal analgesics.

Preclinical Evidence and Efficacy

In multiple in vivo models of pain, including tail-flick, hot-plate, and chemotherapy-induced neuropathic pain, SR-17018 consistently outperformed morphine with:

• Prolonged analgesic effects

• Little to no development of tolerance after repeated dosing

• Comparable potency to morphine on Day 1 and Day 7

• Improved performance in chronic pain models, including paclitaxel-induced neuropathy

SR-17018 even demonstrated efficacy in morphine-tolerant animals, highlighting its potential use in opioid rotation strategies or in patients who no longer respond well to first-line opioids.

Dosage Guidelines (Preclinical Reference)

In rodent studies, effective oral doses range from 12 mg/kg to 48 mg/kg/day. While this does not translate directly to human dosing, it provides a foundation for future clinical dosing studies.

Side Effects and Safety Profile

Compared to classical opioids, SR-17018 has demonstrated a reduced side effect burden: