Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants
Le Wang, Xushuo Zhu, Bo Wang, Yijing Wang, Mengqi Wang, Shuping Yang, Chenhe Su, Junbiao Chang, Bo Zhu
Abstract
This study aimed to develop novel rapid-acting antidepressants with sustained efficacy and favorable safety profiles. We designed and synthesized a series of fluorine-containing scopolamine analogues and evaluated their antidepressant potential. In vitro cytotoxicity assays showed that most of these compounds exhibited minimal toxicity against neuronal and non-neuronal mammalian cell lines (IC 50 > 100 μM). The antidepressant activities of the compounds were evaluated using the tail suspension test, and S -3a was identified as a lead compound with potent and sustained antidepressant effects. Behaviorally, S -3a alleviated depressive symptoms in mice and displayed a higher cognitive safety margin than scopolamine. Toxicological assessments confirmed S -3a ’s safety, while pharmacokinetics showed a rapid clearance (half-life: 16.6 min). Mechanistically, S -3a antagonized M 1 receptors and elevated BDNF levels, suggesting its potential as an antidepressant for further exploration.