Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression |
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| Affiliation: | 1. Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea;2. Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea;3. Center for Neuroscience, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea;4. Department of Neuroscience, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea;5. School of Medicine, Chosun University, Dong-gu, Kwangju 501-759, Republic of Korea;6. Pharmacology Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Republic of Korea;7. Department of Biological Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea;1. Talent Development Centre, Indian Institute of Science, Challakere Campus, Chitradurga, 577536, India;2. Department of Chemistry, Mangalore University, Mangalagangotri, Mangalore, 574199, India;3. Department of Organic Chemistry, Indian Institute of Science, Bangalore, 560012, India;1. State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;2. Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA;1. Clermont Université, Université d''Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France;2. Inserm, U 990, F-63000 Clermont-Ferrand, France;3. Centre Jean Perrin, F-63011 Clermont-Ferrand, France;4. Laboratoires CYCLOPHARMA, Biopôle Clermont-Limagne, Saint-Beauzire F-63360, France;5. CEA, Service Hospitalier Frédéric Joliot, F-91406 Orsay, France |
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| Abstract: | 5-HT7 receptor (5-HT7R) is a promising target for the treatment of depression and neuropathic pain. 5-HT7R antagonists exhibited antidepressant effects, while the agonists produced strong anti-hyperalgesic effects. In our efforts to discover selective 5-HT7R antagonists or agonists, N-biphenylylmethyl 2-methoxyphenylpiperazinylalkanamides 1 were designed, synthesized, and biologically evaluated against 5-HT7R. Among the synthesized compounds, N-2′-chlorobiphenylylmethyl 2-methoxyphenylpiperazinylpentanamide 1–8 showed the best binding affinity with a Ki value of 8.69 nM and it was verified as a novel antagonist according to functional assays. The compound 1–8 was very selective over 5-HT1DR, 5-HT2AR, 5-HT3R, 5-HT5AR and 5-HT6R and moderately selective over 5-HT1AR, 5-HT1BR and 5-HT2CR. The novel 5-HT7R antagonist 1–8 exhibited an antidepressant effect at a dose of 25 mg/kg in the forced swimming test in mice and showed a U-shaped dose–response curve which typically appears in 5-HT7R antagonists such as SB-269970 and lurasidone. |
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| Keywords: | Serotonin receptor 5-HT7R Antagonist Depression Antidepressant |
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