Kim Youngjae, Yeom Miyoung, Tae Jinsung, Rhim Hyewhon, Choo Hyunah
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.
Center for Neuro-Medicine, Brain Research Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Eur J Med Chem. 2016 Mar 3;110:302-10. doi: 10.1016/j.ejmech.2016.01.043. Epub 2016 Jan 25.
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.
为了发现一种用于治疗抑郁症的新型5-HT7R拮抗剂，我们设计了N-酰基咔唑衍生物，并对其进行了合成及针对5-HT7R的生物学评估。在总共合成的30种化合物中，四种化合物27 - 30表现出良好的结合亲和力，其Ki值<100 nM。化合物28，即1-(9H-咔唑-9-基)-6-(4-(2-甲氧基苯基)哌嗪-1-基)己烷-1-酮，对其他血清素受体亚型表现出良好的选择性，并且在功能测定后被证明是一种新型的选择性5-HT7R拮抗剂。化合物28在hERG通道上表现出适度的活性，并且在微粒体稳定性测试中具有良好的稳定性。化合物28展现出良好的药代动力学特征，口服生物利用度为67.8%，并且对大脑具有良好的渗透性。化合物28还在体内抑郁症动物模型中进行了测试，并在强迫游泳试验中显示出抗抑郁作用。因此，选择性5-HT7R拮抗剂28可被视为发现新型5-HT7R拮抗剂作为抗抑郁药的良好先导化合物。
