Design and structural optimization of lappaconitine derivatives as Nav1.7 inhibitors with improved analgesic efficacy and reduced lethality in mice.

Lappaconitine (LA), a diterpenoid alkaloid with analgesic properties, is limited clinically by its narrow safety margin. To overcome this, we synthesized novel LA derivatives modified at the 20-N position to enhance Nav1.7 potency and reduce lethality. Systematic SAR studies identified representative compound 39 for further characterization. Compound 39 inhibited human Nav1.7 (IC50 = 2.87 ± 0.19 μM), exhibiting an 8.6-fold increase in potency over LA (IC50 = 24.71 ± 1.64 μM). This translated to superior suppression of sodium currents and action potential firing in DRG neurons. In a mouse postoperative pain model, intraplantar compound 39 (5-10 μg/site) provided more potent analgesia against mechanical allodynia than LA. Critically, compound 39 showed a >10-fold improved safety margin (LD50 = 47.5 mg/kg i.v. vs. LA's 4.6 mg/kg i.v.), positioning it as a promising analgesic with an improved acute safety profile for pain management.