Synthesis of N-Alkyl-Carbazole Derivatives as 5-HT7R Antagonists

Youngjae Kim, Miyoung Yeom, Soyeon Lee, Jinsung Tae, Hak Joong Kim, Hyewhon Rhim, Jihye Seong, Kyung Il Choi, Sun Joon Min, Hyunah Choo

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

We designed and synthesized a series of N-alkyl-carbazoles with different alkyl chains and amine moieties, and biological evaluation was performed to discover novel 5-HT7R antagonists. Among 27 synthesized compounds, 20, 21, 23, and 24 showed excellent binding affinities to 5-HT7R (Ki = 65, 64, 55, and 31 nM, respectively), and good selectivity profiles over other serotonin receptors. In functional assays, those compounds showed weak antagonistic activities against 5-HT7R. In particular, the compound 24, 2-(4-(5-(9H-carbazol-9-yl)pentyl)piperazin-1-yl)phenol, could be considered as a potent and selective 5-HT7R ligand with weak antagonistic effect. From the molecular docking study, the aromatic hydroxyl group in 24 was shown to play an important role in binding to 5-HT7R through a hydrogen bonding interaction with Asp142 in the ligand binding pocket of 5-HT7R.

Original languageEnglish
Pages (from-to)1083-1089
Number of pages7
JournalBulletin of the Korean Chemical Society
Volume39
Issue number9
DOIs
Publication statusPublished - 2018 Sep 1

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Carbazoles
Ligands
Derivatives
Serotonin Receptors
Phenol
Hydroxyl Radical
Amines
Assays
Hydrogen bonds
carbazole
compound 20
N-dodecyl-L-lysine amide

Keywords

  • 5-HT receptor
  • Antagonist
  • GPCR
  • N-alkyl-carbazole
  • Serotonin

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Synthesis of N-Alkyl-Carbazole Derivatives as 5-HT7R Antagonists. / Kim, Youngjae; Yeom, Miyoung; Lee, Soyeon; Tae, Jinsung; Kim, Hak Joong; Rhim, Hyewhon; Seong, Jihye; Choi, Kyung Il; Min, Sun Joon; Choo, Hyunah.

In: Bulletin of the Korean Chemical Society, Vol. 39, No. 9, 01.09.2018, p. 1083-1089.

Research output: Contribution to journalArticle

Kim, Y, Yeom, M, Lee, S, Tae, J, Kim, HJ, Rhim, H, Seong, J, Choi, KI, Min, SJ & Choo, H 2018, 'Synthesis of N-Alkyl-Carbazole Derivatives as 5-HT7R Antagonists', Bulletin of the Korean Chemical Society, vol. 39, no. 9, pp. 1083-1089. https://doi.org/10.1002/bkcs.11555
Kim, Youngjae ; Yeom, Miyoung ; Lee, Soyeon ; Tae, Jinsung ; Kim, Hak Joong ; Rhim, Hyewhon ; Seong, Jihye ; Choi, Kyung Il ; Min, Sun Joon ; Choo, Hyunah. / Synthesis of N-Alkyl-Carbazole Derivatives as 5-HT7R Antagonists. In: Bulletin of the Korean Chemical Society. 2018 ; Vol. 39, No. 9. pp. 1083-1089.
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AB - We designed and synthesized a series of N-alkyl-carbazoles with different alkyl chains and amine moieties, and biological evaluation was performed to discover novel 5-HT7R antagonists. Among 27 synthesized compounds, 20, 21, 23, and 24 showed excellent binding affinities to 5-HT7R (Ki = 65, 64, 55, and 31 nM, respectively), and good selectivity profiles over other serotonin receptors. In functional assays, those compounds showed weak antagonistic activities against 5-HT7R. In particular, the compound 24, 2-(4-(5-(9H-carbazol-9-yl)pentyl)piperazin-1-yl)phenol, could be considered as a potent and selective 5-HT7R ligand with weak antagonistic effect. From the molecular docking study, the aromatic hydroxyl group in 24 was shown to play an important role in binding to 5-HT7R through a hydrogen bonding interaction with Asp142 in the ligand binding pocket of 5-HT7R.

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