Aryl Biphenyl‐3‐ylmethylpiperazines as 5‐HT7 Receptor Antagonists |
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| Authors: | Jeeyeon Kim Youngjae Kim Prof Jinsung Tae Miyoung Yeom Prof Bongjin Moon Dr Xi‐Ping Huang Prof Bryan L Roth Kangho Lee Dr Hyewhon Rhim Prof Il Han Choo Prof Youhoon Chong Dr Gyochang Keum Dr Ghilsoo Nam Prof Hyunah Choo |
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| Affiliation: | 1. Center for Neuro‐Medicine, Korea Institute of Science and Technology, Seongbuk‐gu, Seoul 136‐791 (Korea);2. Department of Chemistry, Yonsei University, Seodaemun‐gu, Seoul 120‐749 (Korea);3. Department of Chemistry, Sogang University, Mapo‐gu, Seoul 121‐742 (Korea);4. National Institute of Mental Health Psychoactive Drug Screening Program, Division of Medicinal Chemistry and Natural Products, and Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (USA);5. Center for Neuroscience, Korea Institute of Science and Technology, Seongbuk‐gu, Seoul 136‐791 (Korea);6. Department of Neuroscience, University of Science and Technology, Gajungro 217, Youseong‐gu, Daejeon 305‐350 (Korea);7. School of Medicine, Chosun University, Pilmoondaero 309, Dong‐gu, Kwangju 501‐759 (Korea);8. Department of Bioscience and Biotechnology, Konkuk University, Gwangjin‐gu, Seoul 143‐701 (Korea);9. Center for Neuro‐Medicine, Korea Institute of Science and Technology, Seongbuk‐gu, Seoul 136‐791 (Korea)The two corresponding authors contributed equally to this work.;10. Department of Biological Chemistry, University of Science and Technology, Gajungro 217, Youseong‐gu, Daejeon 305‐350 (Korea)The two corresponding authors contributed equally to this work. |
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| Abstract: | The 5‐HT7 receptor (5‐HT7R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5‐HT7R antagonist SB‐269970 exhibited antidepressant‐like activity, whereas systemic administration of the 5‐HT7R agonist AS‐19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5‐HT7R antagonists or agonists, aryl biphenyl‐3‐ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5‐HT7R. Among the synthesized compounds, 1‐(2′‐methoxy‐(1,1′‐biphenyl)‐3‐yl]methyl)‐4‐(2‐methoxyphenyl)piperazine ( 28 ) was the best binder to the 5‐HT7R (pKi=7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5‐HT7R over other serotonin receptor subtypes, such as 5‐HT1R, 5‐HT2R, 5‐HT3R, and 5‐HT6R. In a molecular modeling study, the 2‐methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function. |
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| Keywords: | antagonists biaryls aryl piperazines receptors structure– activity relationships |
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