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

## TL;DR

This study develops new compounds that act as both 5-HT7 receptor blockers and sodium channel inhibitors, showing potential for treating depression and anxiety.

## Contribution

The paper introduces novel dual-action compounds combining 5-HT7 antagonism and sodium channel inhibition for mental health treatment.

## Key findings

- Compounds 10 and 20 showed high 5-HT7 receptor affinity and strong sodium channel inhibition.
- Compound 10 had lower cytotoxicity and better metabolic stability than compound 20.
- Compound 10 demonstrated antidepressant and anxiolytic effects in mice but failed to reduce neuropathic pain.

## Abstract

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 (Ki < 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.