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Molecules 2016, 21(8), 1070; doi:10.3390/molecules21081070

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

1
Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile
2
Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Lira 85, 5th Floor, Santiago 8330074, Chile
3
Facultad de Ciencia, Universidad San Sebastián, Lota 2465, Providencia 7510157, Santiago, Chile
4
Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Casilla 5030, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, Chile
5
Departamento de Química-Física, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Jean Jacques Vanden Eynde
Received: 3 May 2016 / Revised: 6 August 2016 / Accepted: 8 August 2016 / Published: 16 August 2016
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [11017 KB, uploaded 16 August 2016]   |  

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. View Full-Text
Keywords: arylsulfonylindole; 5-HT6 receptor antagonists; binding affinity; arylpiperazines arylsulfonylindole; 5-HT6 receptor antagonists; binding affinity; arylpiperazines
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Vera, G.; Lagos, C.F.; Almendras, S.; Hebel, D.; Flores, F.; Valle-Corvalán, G.; Pessoa-Mahana, C.D.; Mella-Raipán, J.; Montecinos, R.; Recabarren-Gajardo, G. Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation. Molecules 2016, 21, 1070.

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