Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants.

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.