Some natural alkaloids from medicinal plants, such as yohimbine and its derivatives, have been reported with adrenoceptor (AR) α2 subtypes inhibiting activity. In trying to address the possible mechanism of the action, a set of homology models of AR α2 was built based on MOE. After that, docking and molecular dynamics methods were used to investigate the binding modes of yohimbine and its 2 derivatives in the active pocket of adrenoceptor α2 subtype A, B, and C. The key interactions between the 3 ligands and the 3 receptors were mapped. Binding mode analysis presents a strong identity in the key residues in each subtype. Only a few differences play the key role in modulating selectivity of yohimbine and its derivatives. These results can guide the design of new selective AR α2 inhibitors.