Halogen bonding enhances activity in a series of dual 5-HT 6 /D 2 ligands designed in a hybrid bioisostere generation/virtual screening protocol

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-HT 6 /D 2 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-HT 6 /D 2 ligands also showed affinity for 5-HT 7 R and 5-HT 2A R. The para -chloroaniline derivative was identified as a potent dual 5-HT 6 /5-HT 7 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-HT 6 , D 2 and 5-HT 7 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.