Structure–Activity Relationship Analysis of Fluoxetine for Suppression of Inflammatory Cytokine Production

There is accumulating evidence that selective serotonin reuptake inhibitors (SSRIs), clinically used as antidepressants, have a beneficial effect on inflammatory diseases such as coronavirus disease 2019 (COVID-19). We previously compared the inhibitory effects of five U.S. Food and Drug Administrat...

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 2024/05/13, Vol.47(5), pp.946-954
Main Authors: Takenaka, Yohei, Tanaka, Ryu, Kitabatake, Kazuki, Uchiumi, Fumiaki, Aoki, Shin, Kuramochi, Kouji, Tsukimoto, Mitsutoshi
Format: Article
Language:English
Subjects:
Animals
anti-inflammation
Anti-inflammatory agents
Anti-Inflammatory Agents - chemistry
Anti-Inflammatory Agents - pharmacology
Antidepressants
Cell Line
Coronaviruses
COVID-19
Cytokines
Cytokines - metabolism
Fluoxetine
Fluoxetine - pharmacology
fluoxetine derivative
Inflammation - drug therapy
Inflammatory diseases
interleukin (IL)-6
Interleukin 6
Interleukin-6 - metabolism
macrophage
Macrophages
Macrophages - drug effects
Macrophages - metabolism
Mice
Poly I-C - pharmacology
Polyinosinic:polycytidylic acid
Selective Serotonin Reuptake Inhibitors - chemistry
Selective Serotonin Reuptake Inhibitors - pharmacology
Serotonin uptake inhibitors
Structure-Activity Relationship
TLR3 protein
TLR4 protein
TLR9 protein
Toll-like receptor
Toll-Like Receptor 3 - metabolism
Toll-like receptors
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Summary:There is accumulating evidence that selective serotonin reuptake inhibitors (SSRIs), clinically used as antidepressants, have a beneficial effect on inflammatory diseases such as coronavirus disease 2019 (COVID-19). We previously compared the inhibitory effects of five U.S. Food and Drug Administration (FDA)-approved SSRIs on the production of an inflammatory cytokine, interleukin-6 (IL-6), and concluded that fluoxetine (FLX) showed the most potent anti-inflammatory activity. Here, we investigated the structure–activity relationship of FLX for anti-inflammatory activity towards J774.1 murine macrophages. FLX suppressed IL-6 production induced by the TLR3 agonist polyinosinic-polycytidylic acid (poly(I : C)) with an IC50 of 4.76 µM. A derivative of FLX containing chlorine instead of the methylamino group lacked activity, suggesting that the methylamino group is important for the anti-inflammatory activity. FLX derivatives bearing an N-propyl or N-(pyridin-3-yl)methyl group in place of the N-methyl group exhibited almost the same activity as FLX. Other derivatives showed weaker activity, and the N-phenyl and N-(4-trifluoromethyl)benzyl derivatives were inactive. The chlorine-containing derivative also lacked inhibitory activity against TLR9- or TLR4-mediated IL-6 production. These derivatives showed similar structure–activity relationships for TLR3- and TLR9-mediated inflammatory responses. However, the activities of all amino group-containing derivatives against the TLR4-mediated inflammatory response were equal to or higher than the activity of FLX. These results indicate that the substituent at the nitrogen atom in FLX strongly influences the anti-inflammatory effect.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.b24-00083