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Study on the clarification of molecular and pharmacological structure-activity relationships of 5-HT2A antagonists

Research Project

Project/Area Number 17590231
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionNigata University of Phermacy and Applied Life Sciences

Principal Investigator

NAGATOMO Takafumi  Nigata University of Phermacy and Applied Life Sciences, Faculty of Pharmaceutical Science, Dept. of Pharmacology, Professor (60121240)

Co-Investigator(Kenkyū-buntansha) ONUKI Toshio  Niigata University of Pharmacy and Applied Life Scienses, Faculty of Pharmaceutical Science Dept. of Pharmacology, Assistant (60288230)
SUGIHARA Takumichi  Niigata University of Pharmacy and Applied Life Scienses, Faculty of Pharmaceutical Science Dept. of Organic and Medicinal Chemistry, Professor (40222054)
金子 喜三好  新潟薬科大学, 薬学部, 教授 (90133462)
Project Period (FY) 2005 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Keywords5-HT2A receptors / sarpogrelate / modeling / structure-activity relationships / inverse agonist / constitutively active / インバースアゴニスト / 5-HT_<2A>遮断薬 / NMR / 5-HZ_2遮断薬 / 5-HT_<2A>結合部位
Research Abstract

Mutations producing constitutively active G-protein coupled receptors (GPCRs) have been found in the pathophysiology of several diseases, implying that inverse agonists at the constitutively active receptors may have preferred therapeutic applications. Because of the involvement of 5-HT_<2A> receptors in mediating many cardiovascular diseases, constitutively active mutants of the 5-HT_<2A> receptor may be responsible for the disease states. Thus, the purpose of the present study was to investigate the inverse agonist activity of sarpogrelate, a selective 5-HT_<2A>-receptor antagonist, and its active metabolite, M-1; and we compared their activities with those of other 5-HT_<2A>-receptor antagonists such as ritanserin, ketanserin, and cyproheptadine. Using a constitutively active mutant (C322K) of the human 5-HT_<2A> receptor, we demonstrated that like other 5-HT_<2A>-receptor antagonists, sarpogrelate acts as a potent inverse agonist by significantly reducing basal inositol phosphate (IP) levels. However, there were no significant differences between sarpogrelate and other 5-HT_<2A>-receptor antagonists for their inverse agonist activity. Compared with the wild type receptor, mutant receptor displayed significantly higher affinity for 5-HT and lower affinity for sarpogrelate. These results indicate that stabilization of the inactive conformation of the 5-HT_<2A> receptor may be a key component of the mechanism of action of sarpogrelate.

Report

(4 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • Research Products

    (11 results)

All 2007 2006

All Journal Article (8 results) (of which Peer Reviewed: 3 results) Presentation (3 results)

  • [Journal Article] Identification of a key amino acid of the human 5-HT_<2B> serotonin receptor important for sarpogrelate binding2007

    • Author(s)
      Habib Abul Muntasir, et. al.
    • Journal Title

      J.Pharmacol.Sci. 104

      Pages: 274-277

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Identification of a key amino acid of the human 5-HT_2B serotonin receptor important for sarpogrelate binding2007

    • Author(s)
      Habib Abul Muntasir
    • Journal Title

      Journal of Pharmacological Sciences 104

      Pages: 274-277

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Identification of a key amino acid of the human 5-HT_<2B> serotonin receptor important for sarpogrelate binding2007

    • Author(s)
      Habib Abul Muntasir, et. al.
    • Journal Title

      J. Pharmacol. Sci. 104

      Pages: 274-277

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inverse agonist activity of sarpogrelate,a selective 5-HT_<2A>-receptor antagonist,at the constitutibly active human 5-HT_<2A> receptor2006

    • Author(s)
      Habib Abul Muntasir, et. al.
    • Journal Title

      J.Pharmacol.Sci. 102

      Pages: 189-195

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Inverse agonist activity of sarpogrelate, a selective 5-HT_2A-receptor antagonist, at the constitubly active human 5-HT2A receptor2006

    • Author(s)
      Habib Abul Muntasir
    • Journal Title

      Journal of Pharmacological Sciences 102

      Pages: 189-195

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Identification of amino acid residues important for sarpogrelate binding to the human 5-hydroxytryptamine2A serotonin receptor2006

    • Author(s)
      Habib Abul Muntasir et al.
    • Journal Title

      Journal of Pharmacological Sciences 102

      Pages: 55-63

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Site-directed mutagenesis of the serotonin 5-hydroxytrptamine2C receptor : Identification of amino acids responsible for sarpogrelate2006

    • Author(s)
      Habib Abul Muntasir et al.
    • Journal Title

      Biological & Pharmaceutical Bulletin 29

      Pages: 1645-1650

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Identification of amino acid residues Important for sarpogrelate binding to the human 5-hydroxytryptamine_<2A> serotonin receptor.2006

    • Author(s)
      Muntasir HA, Rashid M, Komiyama T, Kawakami J, Nagatomo T:
    • Journal Title

      Journal of Pharmacological Science (投稿中)

    • NAID

      10020346174

    • Related Report
      2005 Annual Research Report
  • [Presentation] Mechanism of inverse agonist action of sarpogrelate at the constitutive active human 5-HT_<2A> receptor reveptor revealed by molecular modeling2007

    • Author(s)
      長友 孝文
    • Organizer
      第35回薬物活性シンポジウム
    • Place of Presentation
      広島県歯科医師会館
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Mechanism of inverse agonist action of sarpogrelate at the constitutive active human 5-HT_<2A> receptor revealed by molecular modeling.2007

    • Author(s)
      Muntasir HA, Bhuiyan MA, Hossain M, Ishiguro M, Nagatomo T.
    • Organizer
      35th Drug-Activity Symposium
    • Place of Presentation
      Hiroshima
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Mechanism of inverse agonist action of sarpogrelate at the constitutive active human 5-HT_<2A> receptor revealed by molecular modeling2007

    • Author(s)
      長友 孝文
    • Organizer
      第35回薬物活性シンポジウム
    • Place of Presentation
      広島県歯科医師会館
    • Related Report
      2007 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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