On the basis of our previously described pharmacophore model for serotonin 5-HT6 receptor (5-HT6R) antagonists, we have designed, synthesized, and pharmacologically characterized a series of benzimidazole derivatives 1− 20 that represent a new family of potent antagonists at the human 5-HT6R. Site-directed mutagenesis and a β2-adrenoceptor- based homology model of the 5-HT6R were used to predict the mode of binding of ...