Dual MOR/D3R ligand with a lower D3R/MOR ratio shows reduced abuse-related signals in mice
- Dual ligands fuse the MOR partial agonist TRV734 with a D3R-antagonist trans-cyclopropylamine scaffold, aiming at safer opioid analgesics.
- (R)-LS02-14 and TRV734 gave robust antinociception but similar abuse-liability and respiratory-depression signals.
- (R)-LS01-64, with a much lower D3R/MOR ratio, gave modest analgesia but weaker reinforcing and conditioned-reward effects and minimal respiratory impact.
💡 Points
The data argue that the D3R/MOR balance, not mere D3R engagement, sets the behavioral profile, and the best safety came with less analgesia. That is the familiar trade-off, so the open question is whether a ratio exists that keeps efficacy while retaining the reward-dampening effect.