Novel Dual 5-HT₇ Antagonists and Sodium Channel Inhibitors as Potential Therapeutic Agents with Antidepressant and...

Background/Objectives: The study aimed to pharmacologically evaluate dually acting ligands, 5-HT₇ antagonists and sodium channel inhibitors, as potential therapeutic agents for the treatment of depression, anxiety, and neuropathic pain. The designed dual ligands combined structural fragments of LP-12 (a 5-HT₇ receptor ligand) and phenytoin (a sodium channel blocker). Methods: A series of 1-(2-biphenyl)piperazine derivatives with a hydantoin core was synthesized and evaluated for 5-HT₇ receptor affinity and sodium channel inhibition. The most potent ligands were further analyzed using molecular docking, cytotoxicity assays (MTT, LDH), and in vitro metabolism studies, including microsomal stability and CYP450 inhibition. In vivo pharmacological effects were assessed in behavioral models: forced swim test, four-plate test, and a streptozotocin (STZ)-induced diabetic neuropathy model in mice. Results: Compounds 10 and 20 exhibited high 5-HT₇ receptor affinity (K_i < 10 nM) and potent sodium channel inhibition (>80% at 1 µM). Docking studies revealed binding modes consistent with established 5-HT₇ ligands. Compound 10 showed lower cytotoxicity than compound 20 in both HepG2 and SH-SY5Y cells and was therefore selected for further evaluation. Metabolic profiling indicated improved microsomal stability relative to verapamil and a low risk of CYP-mediated drug-drug interactions. In vivo, compound 10 produced significant antidepressant- and anxiolytic-like effects, though it failed to reduce neuropathic pain symptoms in the STZ-induced model. Conclusions: Compound 10 shows potential for mood disorder treatment, but further refinement may be needed to improve analgesic efficacy.