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The α_2A adrenergic receptor (α_2A-AR) serves as a critical molecular target for sedatives and analgesics. However, α_2A-AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold α_2A-AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential α_2A-AR agonists with novel scaffold. Our results showed that compounds <b>SY-15</b> and <b>SY-17</b> exhibited significant biological effects in the preliminary evaluation of protein kinase A (PKA) redistribution assays. They also reduced levels of intracellular cyclic adenosine monophosphate (cAMP) in a dose-dependent manner. Upon treatment of the cells with 100 μM concentrations of <b>SY-15</b> and <b>SY-17</b>, there was a respective decrease in the intracellular cAMP levels by 63.43% and 53.83%. Subsequent computational analysis was conducted to elucidate the binding interactions of <b>SY-15</b> and <b>SY-17</b> with the α_2A-AR. The binding free energies of <b>SY-15</b> and <b>SY-17</b> calculated by MD simulations were −45.93 and −71.97 kcal/mol. MD simulations also revealed that both compounds act as bitopic agonists, occupying the orthosteric site and a novel exosite of the receptor simultaneously. Our findings of integrative computational and experimental approaches could offer the potential to enhance ligand affinity and selectivity through dual-site occupancy and provide a novel direction for the rational design of sedatives and analgesics.