期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 3, 页码 1357-1369出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm901672k
关键词
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资金
- Spanish Ministerio de Educacion (MEC) [SAF-2007/67008]
- Comunidad Autonoma de Madrid (CAM) [S-SAL249-2006]
- Instituto de Salud Carlos III [RD07/0067/0008]
- Fundacion Ramon Arecesand MEC
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 beta(2)-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.
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