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.
Bibliographical noteFunding 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).
All Science Journal Classification (ASJC) codes
- Drug Discovery
- Organic Chemistry