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.
authors: Center for Neuro-Medicine, Brain Research Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Youngjae
authors: Y
authors: Kim
authors: Center for Neuro-Medicine, Brain Research Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors: Miyoung
authors: M
authors: Yeom
authors: Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Jinsung
authors: J
authors: Tae
authors: Center for Neuroscience, Korea Institute of Science and Technology, Sueongbuk-gu, Seoul 136-791, Republic of Korea; Department of Neuroscience, University of Science and Technology, Youseong-gu, Daejeon 305-350, Republic of Korea.
authors: Hyewhon
authors: H
authors: Rhim
authors: Center for Neuro-Medicine, Brain Research Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, University of Science and Technology, Youseong-gu, Daejeon 305-350, Republic of Korea. Electronic address: hchoo@kist.re.kr.
authors: Hyunah
authors: H
authors: Choo
mesh_terms: D000215:Acylation; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016466:CHO Cells; D002227:Carbazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D002227:Carbazoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor
keywords: 5-HT(7)R; Antagonist; Depression; GPCR; N-Acyl-carbazole; Serotonin