Novel N-acyl-carbazole derivatives as 5-HT7R antagonists

Youngjae Kim; Miyoung Yeom; Jinsung Tae; Hyewhon Rhim; Hyunah Choo

doi:10.1016/j.ejmech.2016.01.043

Novel N-acyl-carbazole derivatives as 5-HT₇R antagonists

Youngjae Kim, Miyoung Yeom, Jinsung Tae, Hyewhon Rhim, Hyunah Choo

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

To discover a novel 5-HT₇R antagonist for treatment of depression, we designed N-acyl-carbazole derivatives which were synthesized and biologically evaluated against 5-HT₇R. Among total 30 compounds synthesized, four compounds 27-30 showed good binding affinities with K_i values of <100 nM. The compound 28, 1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one, showed good selectivity over other serotonin receptor subtypes and turned out to be a novel selective 5-HT₇R antagonist following functional assays. The compound 28 showed moderate activity on hERG channel and good stability in microsomal stability test. The compound 28 exhibited a good pharmacokinetic profile with 67.8% oral bioavailability and good penetration to the brain. The compound 28 was also tested in in vivo depression animal model and showed antidepressant effect in the forced swimming test. Therefore, the selective 5-HT₇R antagonist 28 can be considered as a good lead for discovery of novel 5-HT₇R antagonists as antidepressants.

Original language	English
Pages (from-to)	302-310
Number of pages	9
Journal	European Journal of Medicinal Chemistry
Volume	110
DOIs	https://doi.org/10.1016/j.ejmech.2016.01.043
Publication status	Published - 2016 Mar 3

Bibliographical note

Funding Information:
This research was supported by the Basic Science Research Program (NRF-2013-R1A1A2A10009907) funded by the National Research Foundation of Korea (NRF). Additional funding was provided by the Korea Institute of Science and Technology (KIST) Institutional Program (2E25580, 2E25473, and 2E25240). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (contract: HHSN-271-2008-00025-C).

Publisher Copyright:
© 2016 Elsevier Masson SAS. All rights reserved.

All Science Journal Classification (ASJC) codes

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2016.01.043

Cite this

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title = "Novel N-acyl-carbazole derivatives as 5-HT7R antagonists",

abstract = "To discover a novel 5-HT7R antagonist for treatment of depression, we designed N-acyl-carbazole derivatives which were synthesized and biologically evaluated against 5-HT7R. Among total 30 compounds synthesized, four compounds 27-30 showed good binding affinities with Ki values of <100 nM. The compound 28, 1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one, showed good selectivity over other serotonin receptor subtypes and turned out to be a novel selective 5-HT7R antagonist following functional assays. The compound 28 showed moderate activity on hERG channel and good stability in microsomal stability test. The compound 28 exhibited a good pharmacokinetic profile with 67.8% oral bioavailability and good penetration to the brain. The compound 28 was also tested in in vivo depression animal model and showed antidepressant effect in the forced swimming test. Therefore, the selective 5-HT7R antagonist 28 can be considered as a good lead for discovery of novel 5-HT7R antagonists as antidepressants.",

author = "Youngjae Kim and Miyoung Yeom and Jinsung Tae and Hyewhon Rhim and Hyunah Choo",

note = "Funding Information: This research was supported by the Basic Science Research Program (NRF-2013-R1A1A2A10009907) funded by the National Research Foundation of Korea (NRF). Additional funding was provided by the Korea Institute of Science and Technology (KIST) Institutional Program (2E25580, 2E25473, and 2E25240). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (contract: HHSN-271-2008-00025-C). Publisher Copyright: {\textcopyright} 2016 Elsevier Masson SAS. All rights reserved.",

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AU - Kim, Youngjae

AU - Yeom, Miyoung

AU - Tae, Jinsung

AU - Rhim, Hyewhon

AU - Choo, Hyunah

N1 - Funding Information: This research was supported by the Basic Science Research Program (NRF-2013-R1A1A2A10009907) funded by the National Research Foundation of Korea (NRF). Additional funding was provided by the Korea Institute of Science and Technology (KIST) Institutional Program (2E25580, 2E25473, and 2E25240). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (contract: HHSN-271-2008-00025-C). Publisher Copyright: © 2016 Elsevier Masson SAS. All rights reserved.

PY - 2016/3/3

Y1 - 2016/3/3

N2 - To discover a novel 5-HT7R antagonist for treatment of depression, we designed N-acyl-carbazole derivatives which were synthesized and biologically evaluated against 5-HT7R. Among total 30 compounds synthesized, four compounds 27-30 showed good binding affinities with Ki values of <100 nM. The compound 28, 1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one, showed good selectivity over other serotonin receptor subtypes and turned out to be a novel selective 5-HT7R antagonist following functional assays. The compound 28 showed moderate activity on hERG channel and good stability in microsomal stability test. The compound 28 exhibited a good pharmacokinetic profile with 67.8% oral bioavailability and good penetration to the brain. The compound 28 was also tested in in vivo depression animal model and showed antidepressant effect in the forced swimming test. Therefore, the selective 5-HT7R antagonist 28 can be considered as a good lead for discovery of novel 5-HT7R antagonists as antidepressants.

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