Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2016-08-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/21/8/1070 |
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| author | Gonzalo Vera Carlos F. Lagos Sebastián Almendras Dan Hebel Francisco Flores Gissella Valle-Corvalán C. David Pessoa-Mahana Jaime Mella-Raipán Rodrigo Montecinos Gonzalo Recabarren-Gajardo |
| author_facet | Gonzalo Vera Carlos F. Lagos Sebastián Almendras Dan Hebel Francisco Flores Gissella Valle-Corvalán C. David Pessoa-Mahana Jaime Mella-Raipán Rodrigo Montecinos Gonzalo Recabarren-Gajardo |
| author_sort | Gonzalo Vera |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T11:02:50Z |
| format | Article |
| id | doaj.art-cf1f81bde6e74fedae6eef237b51af6e |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-10T11:02:50Z |
| publishDate | 2016-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-cf1f81bde6e74fedae6eef237b51af6e2022-12-22T01:51:39ZengMDPI AGMolecules1420-30492016-08-01218107010.3390/molecules21081070molecules21081070Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological EvaluationGonzalo Vera0Carlos F. Lagos1Sebastián Almendras2Dan Hebel3Francisco Flores4Gissella Valle-Corvalán5C. David Pessoa-Mahana6Jaime Mella-Raipán7Rodrigo Montecinos8Gonzalo Recabarren-Gajardo9Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, ChileDepartment of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Lira 85, 5th Floor, Santiago 8330074, ChileDepartamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, ChileDepartamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, ChileDepartamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, ChileInstituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Casilla 5030, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, ChileDepartamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, ChileInstituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Casilla 5030, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, ChileDepartamento de Química-Física, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, ChileDepartamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, ChileBased 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.http://www.mdpi.com/1420-3049/21/8/1070arylsulfonylindole5-HT6 receptor antagonistsbinding affinityarylpiperazines |
| spellingShingle | Gonzalo Vera Carlos F. Lagos Sebastián Almendras Dan Hebel Francisco Flores Gissella Valle-Corvalán C. David Pessoa-Mahana Jaime Mella-Raipán Rodrigo Montecinos Gonzalo Recabarren-Gajardo Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation Molecules arylsulfonylindole 5-HT6 receptor antagonists binding affinity arylpiperazines |
| title | Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation |
| title_full | Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation |
| title_fullStr | Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation |
| title_full_unstemmed | Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation |
| title_short | Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation |
| title_sort | extended n arylsulfonylindoles as 5 ht6 receptor antagonists design synthesis amp biological evaluation |
| topic | arylsulfonylindole 5-HT6 receptor antagonists binding affinity arylpiperazines |
| url | http://www.mdpi.com/1420-3049/21/8/1070 |
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