title: Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression.
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 8.69nM 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 25mg/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.
authors.affiliation: Center for Neuro-Medicine, 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.forename: Youngjae
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors.forename: Jinsung
authors.initials: J
authors.lastname: Tae
authors.affiliation: Center for Neuroscience, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Neuroscience, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea.
authors.forename: Kangho
authors.initials: K
authors.lastname: Lee
authors.affiliation: Center for Neuroscience, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Neuroscience, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea.
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
authors.affiliation: School of Medicine, Chosun University, Dong-gu, Kwangju 501-759, Republic of Korea.
authors.forename: Il Han
authors.initials: IH
authors.lastname: Choo
authors.affiliation: Pharmacology Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Republic of Korea.
authors.forename: Heeyeong
authors.initials: H
authors.lastname: Cho
authors.affiliation: Pharmacology Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Republic of Korea.
authors.forename: Woo-Kyu
authors.initials: WK
authors.lastname: Park
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea. Electronic address: gkeum@kist.re.kr.
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea. Electronic address: hchoo@kist.re.kr.
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy*; D057809:HEK293 Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013550:Swimming
chemical_list: D000577:Amides; D000928:Antidepressive Agents; D010879:Piperazines; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor
keywords: 5-HT7R; Antagonist; Antidepressant; Depression; Serotonin receptor