Antiemetic Efficacy of Esculetin via Dopaminergic, Serotonergic, and Muscarinic Pathway Modulation: Insights From In Vivo and In Silico Studies

Esculetin (ELN), a naturally occurring coumarin derivative, possesses a range of pharmacological activities, yet its antiemetic potential remains underexplored. This study assessed the efficacy of ELN against copper sulfate pentahydrate (CuSO4.5H2O)-induced emesis through a combined in vivo and in silico approach. In a validated chick emesis model, 3-day-old chicks were orally administered CuSO₄·5H2O (50 mg/kg) to induce vomiting. Standard antiemetic agents domperidone (DOM-6 mg/kg), ondansetron (OND-5 mg/kg), and hyoscine (HYO-21 mg/kg) served as reference drugs. ELN was tested at doses of 5, 10, and 20 mg/kg, both as monotherapy and in combination with standard drugs, to evaluate dose-response relationships and potential drug-drug interactions. ELN-20 demonstrated the most pronounced efficacy among the individual doses, producing the longest latency, surpassing the standard treatments OND, DOM, and HYO. Furthermore, the combination therapies ELN-10 + DOM-6 and ELN-10 + HYS-21 showed marked improvements, suggesting a synergistic interaction that enhances the overall therapeutic effect. Molecular docking studies were performed to investigate ELN's binding affinity (BA) with key emetogenic receptors, including dopaminergic (D2, D3), serotonergic (5-HT3), and muscarinic (M1-M5) subtypes. Docking results demonstrated supportive, moderate binding across dopaminergic (D2, D3), serotonergic (5-HT3), and muscarinic (M1-M5) receptors, which, together with in vivo efficacy and synergistic effects with standard antiemetics, suggest a multi-receptor involvement rather than definitive receptor blockade. Given its efficacy and multi-target profile, ELN shows promise as a novel candidate for emesis management, warranting further preclinical and clinical investigations.