Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants.
J Med Chem
; 67(7): 5391-5420, 2024 Apr 11.
Article
in En
| MEDLINE
| ID: mdl-38354305
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 (IC50 > 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 M1 receptors and elevated BDNF levels, suggesting its potential as an antidepressant for further exploration.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Scopolamine
/
Fluorine
Limits:
Animals
Language:
En
Journal:
J Med Chem
/
J. med. chem
/
Journal of medicinal chemistry
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
United States