Extended N-Arylsulfonylindoles As 5-HT₆ Receptor Antagonists: Design, Synthesis & Biological Evaluation

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2016 Aug 19

PMID 27537868

Citations 6

Authors

Gonzalo Vera

Carlos F Lagos

Sebastian Almendras

Dan Hebel

Francisco Flores

Gissella Valle-Corvalan

C David Pessoa-Mahana

Jaime Mella-Raipan

Rodrigo Montecinos

Gonzalo Recabarren-Gajardo

Affiliations

Soon will be listed here.

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.

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Extended N-Arylsulfonylindoles As 5-HT₆ Receptor Antagonists: Design, Synthesis &amp; Biological Evaluation

Extended N-Arylsulfonylindoles As 5-HT₆ Receptor Antagonists: Design, Synthesis & Biological Evaluation