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Article Dans Une Revue Journal of Medicinal Chemistry Année : 2010

Benzimidazole Derivatives as New Serotonin 5-HT 6 Receptor Antagonists. Molecular Mechanisms of Receptor Inactivation

Lucie P. Pellissier
Sylvie Claeysen
Aline Dumuis
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Résumé

On the basis of our previously described pharmacophore model for serotonin 5-HT(6) receptor (5-HT(6)R) 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-HT(6)R. Site-directed mutagenesis and a beta(2)-adrenoceptor-based homology model of the 5-HT(6)R 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 CH(2)-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-HT(6)R antagonists.
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hal-02483302 , version 1 (18-02-2020)

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Tania de La Fuente, Mar Martín-Fontecha, Jessica Sallander, Bellinda Benhamú, Mercedes Campillo, et al.. Benzimidazole Derivatives as New Serotonin 5-HT 6 Receptor Antagonists. Molecular Mechanisms of Receptor Inactivation. Journal of Medicinal Chemistry, 2010, 53 (3), pp.1357-1369. ⟨10.1021/jm901672k⟩. ⟨hal-02483302⟩
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