title: Extended N-Arylsulfonylindoles as 5-HT₆ Receptor Antagonists: Design, Synthesis &amp; Biological Evaluation.
abstract: Based on a known pharmacophore model for 5-HT₆ receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT₆ receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT₆ receptor functional assays. Compounds 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol (4b), 1-(1-(4-iodophenylsulfonyl)-1H-indol-3-yl)-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethanol (4g) and 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-(naphthalen-1-ylsulfonyl)-1H-indol-3-yl)ethanol (4j) showed the best binding affinity (4b pKi = 7.87; 4g pKi = 7.73; 4j pKi = 7.83). Additionally, compound 4j was identified as a highly potent antagonist (IC50 = 32 nM) in calcium mobilisation functional assay.
authors.affiliation: Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile. glvera@uc.cl.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Vera
authors.affiliation: Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Lira 85, 5th Floor, Santiago 8330074, Chile. cflagos@uc.cl.|Facultad de Ciencia, Universidad San Sebastián, Lota 2465, Providencia 7510157, Santiago, Chile. cflagos@uc.cl.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Lagos
authors.affiliation: Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile. sialmend@uc.cl.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Almendras
authors.affiliation: Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile. dnhebel@uc.cl.
authors.forename: Dan
authors.initials: D
authors.lastname: Hebel
authors.affiliation: Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile. fjflores1@uc.cl.
authors.forename: Francisco
authors.initials: F
authors.lastname: Flores
authors.affiliation: Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Casilla 5030, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, Chile. gissella.valle@alumnos.uv.cl.
authors.forename: Gissella
authors.initials: G
authors.lastname: Valle-Corvalán
authors.affiliation: Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile. cpessoa@uc.cl.
authors.forename: C David
authors.initials: CD
authors.lastname: Pessoa-Mahana
authors.affiliation: Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Casilla 5030, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, Chile. jaime.mella@uv.cl.
authors.forename: Jaime
authors.initials: J
authors.lastname: Mella-Raipán
authors.affiliation: Departamento de Química-Física, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile. rmontecinoe@uc.cl.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Montecinos
authors.affiliation: Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile. grecabarren@uc.cl.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Recabarren-Gajardo
mesh_terms: D001190:Arylsulfonates / Q000737:chemistry*; D001665:Binding Sites; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001190:Arylsulfonates; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor
keywords: 5-HT6 receptor antagonists; arylpiperazines; arylsulfonylindole; binding affinity