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

Phytochemical investigation on the aerial parts of <i>Oreomecon nudicaulis</i> 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 (<b>1</b>-<b>4</b>), two isopavine alkaloids oreonudines E (<b>5</b>) and F (<b>6</b>), one rhoeadine alkaloid oreonudine G (<b>7</b>), and one morphinane alkaloid oreonudine H (<b>8</b>), along with 10 previously reported analogues <b>9</b>-<b>18</b>. Their structures were determined by comprehensive spectroscopic and spectrometric analyses, single-crystal X-ray diffraction, and quantum chemical calculations of ECD spectra. <i>In vitro</i> studies using HT22 mouse hippocampal neuronal cells revealed that the previously reported compounds <b>12</b>, <b>15</b>, and <b>16</b> exhibited potent inhibition of serotonin (5-HT) and/or norepinephrine (NE) reuptake. Among them, mecoquitupline (<b>15</b>) 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 <b>15</b> to both serotonin transporter (SERT) and norepinephrine transporter (NET). In contrast, <b>12</b> and <b>16</b> selectively inhibited NE and 5-HT reuptake, respectively, by targeting the corresponding transporters. These findings highlight mecoquitupline (<b>15</b>) as a promising dual-action antidepressant candidate with potent activity.