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

ABSTRACT 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 (CuSO 4 .5H 2 O)‐induced emesis through a combined in vivo and in silico approach. In a validated chick emesis model, 3‐day‐old chicks were orally administered CuSO₄·5H 2 O (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 (D 2 , D 3 ), serotonergic (5‐HT 3 ), and muscarinic (M 1 –M 5 ) subtypes. Docking results demonstrated supportive, moderate binding across dopaminergic (D 2, D 3 ), serotonergic (5‐HT 3 ), and muscarinic (M 1 –M 5 ) 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.