Benzimidazole derivatives as new serotonin 5-HT<inf>6</inf> receptor antagonists. Molecular mechanisms of receptor inactivation

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

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46 Citations (Scopus)

Abstract

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. Sitedirected mutagenesis and a β2- adrenoceptor-based homology model of the 5-HT6Rwere 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. ©2010 America Chemical Society.
Original languageEnglish
Pages (from-to)1357-1369
JournalJournal of Medicinal Chemistry
Volume53
DOIs
Publication statusPublished - 1 Mar 2010

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