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

Molecules

Francisco Flores¹  C. David Pessoa-Mahana¹  Gonzalo Recabarren-Gajardo¹  Dan Hebel¹  Sebastián Almendras¹  Gonzalo Vera¹  Rodrigo Montecinos²  Carlos F. Lagos³  Jaime Mella-Raipán⁴  Gissella Valle-Corvalán⁴ 

[1] Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile;Departamento de Química-Física, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile;Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Lira 85, 5th Floor, Santiago 8330074, Chile;Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Casilla 5030, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, Chile;

关键词: arylsulfonylindole;    5-HT6 receptor antagonists;    binding affinity;    arylpiperazines;   

DOI  :  10.3390/molecules21081070

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown