Synthesis and biological evaluation of (+)-paeoveitol derivatives as novel antidepressants

The antidepressant activity of (+) and (−)-paeoveitol was first evaluated using the forced swimming test (FST), and (+)-paeoveitol showed potential antidepressant activity by decreasing immobility time of mice (by approximately 26.4%) in the FST at a dose of 20 mg/kg. To explore the structure-activi...

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Bibliographic Details
Published in:Medicinal chemistry research 2022, Vol.31 (11), p.2045-2057
Main Authors: Li, Tian-Ze, Huang, Xiao-Yan, Sun, Jin-Jin, Geng, Chang-An, Zhang, Xue-Mei, Chen, Ji-Jun
Format: Article
Language:English
Subjects:
Antidepressants
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Fluoxetine
In vivo methods and tests
Inorganic Chemistry
Medicinal Chemistry
Norepinephrine
Original Research
Pharmacokinetics
Pharmacology/Toxicology
Receptors
Structure-activity relationships
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Summary:The antidepressant activity of (+) and (−)-paeoveitol was first evaluated using the forced swimming test (FST), and (+)-paeoveitol showed potential antidepressant activity by decreasing immobility time of mice (by approximately 26.4%) in the FST at a dose of 20 mg/kg. To explore the structure-activity relationships (SARs) and obtain more potent compounds, twenty derivatives of (+)-paeoveitol were synthesized and evaluated for their agonistic activities on melatonin type I (MT 1 ) and type II (MT 2 ) receptors. As a results, compound 13 with an N -methylpiperazine fragment exhibited obvious effect on MT 1 and MT 2 receptors with EC 50 values of 0.20 and 0.24 mM. Moreover, compound 13 dose-dependently decreased the immobility of mice in the FST and showed an inverted U-shaped dose-effect, and the most efficacious dose (at 40 mg/kg) was comparable to fluoxetine (20 mg/kg) with a reduced immobility time of 29.2% and 34.5%, respectively. In vivo neurochemical assays suggested that compound 13 obviously increased 5 - hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) levels in the mice brain, indicating that its antidepressant effects might be related to the monoaminergic system. In silico ADMET study revealed that 13 has favorable pharmacokinetic properties. These findings suggest that compound 13 could be a potential antidepressant agent. Graphical abstract
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-022-02973-0