Oreonudines A – H, Benzylisoquinoline-Derived Alkaloids with Diverse Skeletons from Oreomecon nudicaulis and Their Antidepressant Activities

Phytochemical investigation on the aerial parts of Oreomecon nudicaulis resulted in the identification of eight new benzylisoquinoline-derived secondary metabolites, including four unusual C-6–N-17 bond cleaved isopavine alkaloids oreonudines A–D (1–4), two isopavine alkaloids oreonudines E (5) and F (6), one rhoeadine alkaloid oreonudine G (7), and one morphinane alkaloid oreonudine H (8), along with 10 previously reported analogues 9–18. Their structures were determined by comprehensive spectroscopic and spectrometric analyses, single-crystal X-ray diffraction, and quantum chemical calculations of ECD spectra. In vitro studies using HT22 mouse hippocampal neuronal cells revealed that the previously reported compounds 12, 15, and 16 exhibited potent inhibition of serotonin (5-HT) and/or norepinephrine (NE) reuptake. Among them, mecoquitupline (15) showed significant inhibitory activity against 5-HT (88.0%) and NE (58.8%) reuptake, outperforming the tricyclic antidepressant amitriptyline (53.6% and 35.5%, respectively), and notably activated the neurotrophic BDNF/CREB signaling pathway. Molecular docking and drug affinity responsive target stability (DARTS) assays further confirmed the binding of 15 to both serotonin transporter (SERT) and norepinephrine transporter (NET). In contrast, 12 and 16 selectively inhibited NE and 5-HT reuptake, respectively, by targeting the corresponding transporters. These findings highlight mecoquitupline (15) as a promising dual-action antidepressant candidate with potent activity.