Get access

Aryl Biphenyl-3-ylmethylpiperazines as 5-HT7 Receptor Antagonists

Authors

  • Jeeyeon Kim,

    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)
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Youngjae Kim,

    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)
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Prof. Jinsung Tae,

    1. Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749 (Korea)
    Search for more papers by this author
  • Miyoung Yeom,

    1. Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791 (Korea)
    2. Department of Chemistry, Sogang University, Mapo-gu, Seoul 121-742 (Korea)
    Search for more papers by this author
  • Prof. Bongjin Moon,

    1. Department of Chemistry, Sogang University, Mapo-gu, Seoul 121-742 (Korea)
    Search for more papers by this author
  • Dr. Xi-Ping Huang,

    1. 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)
    Search for more papers by this author
  • Prof. Bryan L. Roth,

    1. 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)
    Search for more papers by this author
  • Kangho Lee,

    1. Center for Neuroscience, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791 (Korea)
    2. Department of Neuroscience, University of Science and Technology, Gajungro 217, Youseong-gu, Daejeon 305-350 (Korea)
    Search for more papers by this author
  • Dr. Hyewhon Rhim,

    1. Center for Neuroscience, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791 (Korea)
    2. Department of Neuroscience, University of Science and Technology, Gajungro 217, Youseong-gu, Daejeon 305-350 (Korea)
    Search for more papers by this author
  • Prof. Il Han Choo,

    1. School of Medicine, Chosun University, Pilmoondaero 309, Dong-gu, Kwangju 501-759 (Korea)
    Search for more papers by this author
  • Prof. Youhoon Chong,

    1. Department of Bioscience and Biotechnology, Konkuk University, Gwangjin-gu, Seoul 143-701 (Korea)
    Search for more papers by this author
  • Dr. Gyochang Keum,

    1. Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791 (Korea)
    Search for more papers by this author
  • Dr. Ghilsoo Nam,

    Corresponding author
    1. Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791 (Korea)
    • Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791 (Korea)

    Search for more papers by this author
    • The two corresponding authors contributed equally to this work.

  • Prof. Hyunah Choo

    Corresponding author
    1. Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791 (Korea)
    2. Department of Biological Chemistry, University of Science and Technology, Gajungro 217, Youseong-gu, Daejeon 305-350 (Korea)
    • Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791 (Korea)

    Search for more papers by this author
    • The two corresponding authors contributed equally to this work.


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.

Get access to the full text of this article

Ancillary