Methylenedioxy open-loop and closed-loop aporphines designed for the evaluation of potential antidepressants

Abstract

A series of methylenedioxy open-loop and closed-loop aporphine derivatives were designed and synthesized to systematically compare their antidepressant effects and addiction potential. The methylenedioxy open-loop derivatives showed slightly superior antidepressant activity compared with their closed-loop counterparts. Notably, the open-loop derivative Ie demonstrated significantly lower addictive potential than the closed-loop derivative IIe, suggesting that the open-loop methylenedioxy moiety may attenuate the addiction liability of related synthetic antidepressants. Further investigations revealed a significant increase in brain 5-hydroxytryptamine (5-HT) levels following treatment with Ie, which may be attributed to its synergistic effect on downregulating the expression of 5-HT_2A receptors (5-HT_2AR) and serotonin transporters (SERT). Collectively, the results indicate that Ie possesses the most potent and rapid antidepressant activity among the synthesized compounds, outperforming fluoxetine (Flu) in both efficacy and onset of action. These findings suggest that methylenedioxy open-loop aporphines—particularly Ie—hold strong promise as drug candidates for central nervous system modulation.