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

• Published in: Biological & pharmaceutical bulletin Vol. 47; no. 5; pp. 946 - 954
• Main Authors: Takenaka, Yohei, Tanaka, Ryu, Kitabatake, Kazuki, Uchiumi, Fumiaki, Aoki, Shin, Kuramochi, Kouji, Tsukimoto, Mitsutoshi
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 13.05.2024; Japan Science and Technology Agency
• 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; fluoxetine derivative; macrophage; anti-inflammation; Toll-like receptor; interleukin (IL)-6
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b24-00083

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.