A Dual 5-HT7 Receptor Antagonist and Sodium Channel Inhibitor With Antidepressant- and Anxiolytic-Like Activity and Reduced Hepatotoxicity.

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-HT7 receptor and voltage-gated sodium channels. In vitro studies demonstrated that compound 5 exhibits high affinity for the 5-HT7 receptor (Ki = 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-HT7 receptor antagonist (Kb = 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-HT7 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.