A series of structurally constrained analogues based on hybrid compounds containing octahydrobenzo[g or f]quinoline moieties were designed, synthesized, and characterized for their binding to dopamine D2 and D3 receptors expressed in HEK-293 cells. Among the newly developed constrained molecules, trans-octahydrobenzo[f]quinolin-7-ol (8) exhibited the highest affinity for D2 and D3 receptors, the (-)-isomer being the eutomer. Interestingly, this hybrid constrained version 8 showed significant affinity over the corresponding nonhybrid version 1 (representing a constrained version of the aminotetralin structure only) when assayed under same conditions (K(i) of 49.1 and 14.9 nM for 8 vs 380 and 96.0 nM for 1 at D2 and D3, respectively). Similar results were found with other lead hybrid compounds, indicating a contribution of the piperazine moiety in the observed enhanced affinity. On the basis of the data of new lead constrained derivatives and other lead hybrid derivatives developed by us, a unique pharmacophore model was proposed consisting of three pharmacophoric centers, two with aromatic/hydrophobic and one with cationic features.