title: Benzimidazole derivatives as new serotonin 5-HT6 receptor antagonists. Molecular mechanisms of receptor inactivation.
abstract: 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.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: de la Fuente
authors.forename: Mar
authors.initials: M
authors.lastname: Martín-Fontecha
authors.forename: Jessica
authors.initials: J
authors.lastname: Sallander
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.forename: Mercedes
authors.initials: M
authors.lastname: Campillo
authors.forename: Rocío A
authors.initials: RA
authors.lastname: Medina
authors.forename: Lucie P
authors.initials: LP
authors.lastname: Pellissier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Claeysen
authors.forename: Aline
authors.initials: A
authors.lastname: Dumuis
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001667:Binding, Competitive; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D000242:Cyclic AMP