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

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journal contribution
posted on 11.02.2010, 00:00 by Tania de la Fuente, Mar Martín-Fontecha, Jessica Sallander, Bellinda Benhamú, Mercedes Campillo, Rocío A. Medina, Lucie P. Pellissier, Sylvie Claeysen, Aline Dumuis, Leonardo Pardo, María L. López-Rodríguez
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 120 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.