A novel hybrid bioisostere generation/virtual screening method combined with narrowing of chemical space through similarity to compounds that are active at the second target was successfully applied for the development of structurally new dual 5-HT₆/D₂ receptor ligands. Consequently, a series of derivatives of the found hit 1d (N-[2-(dimethylamino)ethyl]-N-(2-phenylethyl)aniline) was synthesized. The most active 5-HT₆/D₂ ligands also showed affinity for 5-HT₇R and 5-HT_2AR. The para-chloroaniline derivative was identified as a potent dual 5-HT₆/5-HT₇ receptor antagonist (K_i = 24 nM and K_b = 30 nM, K_i = 4 nM and K_b = 1.4 nM, respectively). In the case of halogen-containing compounds, interesting structure–activity relationships were observed at 5-HT₆, D₂ and 5-HT₇ receptors, and the ligand–receptor complexes were subsequently examined using a molecular modelling approach that combined quantum-polarized ligand docking (QPLD) and Molecular-Mechanics-Generalized-Born/Surface Area (MM/GBSA) free-energy calculation, which permitted the identification of putative halogen binding pockets.