Here we report a structure-activity relationship (SAR) study of analogues of 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol. Our SAR is focused on introduction of various substitutions in the piperazine ring of the hybrid template. The goal behind this study is to delineate the nature of the binding pocket for N-aryl substitution in the piperazine ring by observing the effect of various hydrophobic and other heteroaromatic substitutions on binding affinity (K(i)), as measured with tritiated spiperone and HEK-293 cells expressing either D(2) or D(3) receptors. Functional activity of selected compounds was assessed with the GTPgammaS binding assay. Compound 8d was the most selective for the D(3) receptor in the spiperone binding assay. An interesting similarity in binding affinity was observed between isoquinoline derivative D-301 and the 2-substituted pyridine derivative 8d, suggesting the importance of relative spatial relationships between the N-atom of the ligand and the molecular determinants of the binding pocket in D(2)/D(3) receptors. Functional activity assays demonstrated high potency and selectivity of (+)-8a and (-)-28b (D(2)/D(3) (ratio of EC(50)): 105 and 202, respectively) for the D(3) receptor and both compounds were more selective compared to the reference drug ropinirole (D(2)/D(3) (ratio of EC(50)): 29.5).