A Dual 5‐HT 7 Receptor Antagonist and Sodium Channel Inhibitor With Antidepressant‐ and Anxiolytic‐Like Activity and Reduced Hepatotoxicity
Anna Czopek, Katarzyna Wójcik‐Pszczoła, Paulina Koczurkiewicz‐Adamczyk, Michał Sapa, Krzysztof Kamiński, Grzegorz Satała, Andrzej J. Bojarski, Agata Siwek, Małgorzata Wolak, Kinga SałatABSTRACT
The aim of this study was to characterize the pharmacological profile of a newly synthesized compound 5 ( R,S) −1‐(5‐{4‐[(1,1'‐biphenyl)‐2‐yl]piperazin‐1‐yl}pentyl)−3',4'‐dihydro‐2' H ‐spiro[imidazolidine‐4,1'‐naphthalene]‐2,5‐dione, designed as a dual‐acting ligand targeting the serotonin 5‐HT 7 receptor and voltage‐gated sodium channels. In vitro studies demonstrated that compound 5 exhibits high affinity for the 5‐HT 7 receptor (K i = 19 nM), comparable to the reference ligand LP‐211, and potent inhibition of sodium channels, markedly stronger than that of phenytoin. Functional assays confirmed that compound 5 acts as a 5‐HT 7 receptor antagonist (K b = 87 nM) with no detectable agonist activity. In addition, the compound showed negligible affinity for the serotonin transporter (SERT), indicating a favorable selectivity profile. Molecular docking studies revealed a stable binding mode of compound 5 within the orthosteric site of the 5‐HT 7 receptor, consistent with known GPCR interaction patterns. Modifications to compound 5 improved its safety by reducing hepatocytotoxicity in HepG2 cells. In vivo behavioral experiments demonstrated significant antidepressant‐like effects in the forced swim test and anxiolytic‐like effects in the four‐plate test in mice.