TY - JOUR
T1 - Benzimidazole derivatives as new serotonin 5-HT6 receptor antagonists. Molecular mechanisms of receptor inactivation
AU - De La Fuente, Tania
AU - Martín-Fontecha, Mar
AU - Sallander, Jessica
AU - Benhamú, Bellinda
AU - Campillo, Mercedes
AU - Medina, Rocío A.
AU - Pellissier, Lucie P.
AU - Claeysen, Sylvie
AU - Dumuis, Aline
AU - Pardo, Leonardo
AU - López-Rodríguez, María L.
PY - 2010/3/1
Y1 - 2010/3/1
N2 - 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.
AB - 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.
U2 - https://doi.org/10.1021/jm901672k
DO - https://doi.org/10.1021/jm901672k
M3 - Article
VL - 53
SP - 1357
EP - 1369
ER -