Carmiseconapine A as a Promising Antidepressant Candidate: An Adenosine 5′-Monophosphate-Activated Protein Kinase Agonist with an Unprecedented Chemical Skeleton

A novel rearranged C20-diterpenoid alkaloid, carmiseconapline A (1), featuring a unique 10,20:11,12-di-seco-napelline skeleton with a fused 5/6/5/6/7 pentacyclic ring system, was isolated from Aconitum carmichaelii Debeaux. Compound 1 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 1 effectively activated adenosine 5′-monophosphate-activated protein kinase (AMPK), protected HT22 cells from mitochondrial dysfunction, and inhibited apoptosis. These findings suggested 1 as a potential AMPK activator for antidepressant development.