Benzimidazole Derivatives as New Serotonin 5-HT₆ Receptor Antagonists. Molecular Mechanisms of Receptor Inactivation

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 antagonist SB-258585 and the new synthesized ligands. Substitution of W6.48, F6.52, or N6.55 by Ala fully impedes compound 4 to block 5-HT-induced activation. Thus, we propose that D3.32 in TM 3 anchors the protonated piperazine ring, the benzimidazole ring expands parallel to EL 2 to hydrogen bond N6.55 in TM 6, and the aromatic ring is placed between TMs 3 and 5 in CH₂-containing compounds and between TMs 3 and 6 in CO-containing compounds. This combined experimental and computational study has permitted to propose the molecular mechanisms by which the new benzimidazole derivatives act as 5-HT₆R antagonists.