CarmiseconapineA as a Promising Antidepressant Candidate:An Adenosine 5′-Monophosphate-Activated Protein Kinase Agonistwith an Unprecedented Chemical Skeleton

A novel rearranged C₂₀-diterpenoid alkaloid, carmiseconapline A (<b>1</b>), featuring a unique 10,20:11,12-di-<i>seco</i>-napelline skeleton with a fused 5/6/5/6/7 pentacyclic ring system, was isolated from Aconitum carmichaelii Debeaux. Compound <b>1</b> exhibited remarkable antidepressive activity, being twice as potent as fluoxetine (10 mg/kg) at 0.06 mg/kg in mice. Further mechanism studies showed that <b>1</b> effectively activated adenosine 5′-monophosphate-activated protein kinase (AMPK), protected HT22 cells from mitochondrial dysfunction, and inhibited apoptosis. These findings suggested <b>1</b> as a potential AMPK activator for antidepressant development.