Assessment of antiemetic potential of schaftoside through modulation of dopaminergic, serotonergic and muscarinic signaling pathways: in vivo and in silico investigations.

Schaftoside (SCF), a natural flavonoid present in numerous plants, exhibits diverse physiological and pharmacological properties. This study explores the antiemetic effects of SCF in response to copper sulfate pentahydrate (CuSO₄.5H₂O)-induced vomiting, employing both in vivo and in silico methods. To induce emesis in chicks, CuSO₄.5H₂O (50 mg/kg) was administered orally. SCF was tested at doses of 5, 10, and 20 mg/kg and compared to standard antiemetics domperidone (DOM-6 mg/kg), ondansetron (OND-5 mg/kg), and hyoscine (HYO-21 mg/kg). The control group received a vehicle, while additional groups received drug combinations to assess synergy or antagonism. Molecular docking and ligand-receptor interactions targeting D₂, D₃, 5HT₃, and M₁-M₅ receptors were analyzed, and SCF's pharmacokinetics (PKs), drug-likeness, and toxicity were evaluated. SCF showed antiemetic effects at higher doses (20 mg/kg), reducing retching (1.8 ± 0.41) and increasing latency (67.6 ± 2.63 s) compared to the vehicle. SCF also enhanced the efficacy of DOM, OND and HYO. The molecular docking results indicated that SCF binds strongly, particularly at M₄ (- 9.7 kcal/mol), with higher affinity than all reference drugs except D₃. Our findings indicate that SCF exerts potent antiemetic effects by modulating the D₂, 5HT₃ and muscarinic receptor pathways. PKs and toxicity profiling revealed that SCF possesses favorable drug-likeness characteristics, good water solubility, moderate skin permeability, favorable metabolic and excretory characteristics as well as promising safety profile. Despite some lacking in PKs properties, its safety profile and efficacy in behavioral models support SCF as a promising candidate for antiemetic drug.