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Having an Anesthetic without adverse effects : The binding sites of dexmedetomidine on adrenoceptor

Research Project

Project/Area Number 09470335
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Anesthesiology/Resuscitation studies
Research InstitutionDepartment of Anesthesiology Kyoto Prefectural University of Medicine

Principal Investigator

MIZOBE Toshiki  M.D., Ph.D. Associate Professor, Department of Anesthesiology, Kyoto Prefectural University of Medicine, 医学部, 講師 (50239266)

Co-Investigator(Kenkyū-buntansha) TANAKA Yoshifumi  M.D., Ph.D. Professor of Chair, Department of Anesthesiology, Kyoto Prefectural University of Medicine, 医学部, 教授 (50079935)
青木 祐司  京都府立医科大学, 医学部, 助手 (90260794)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1998: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1997: ¥4,100,000 (Direct Cost: ¥4,100,000)
Keywordsdexmedetomdine / adrenergic receptor / chimeric receptor / point-mutant receptor / PCR / anesthesia / デクスメデドミジン / 変異受容体 / α_2作動薬 / 静脈麻酔薬 / デキサメデトミジン / 組み換え遺伝子操作
Research Abstract

Dexmedetomidine (DEX) is a subtype non-selective, alpha2 adrenergic agonist developed for anesthetic management because of its sedative/hypnotic, anestheticsparing, analgesic and sympatholytic properties. Each of these properties are thought to be mediated by activation of the alpha2A adrenoceptor subtype. We sought to determine the TMDs on the human alpha2A adrenoceptor subtype which are responsible for binding to DEX in order to design novel subtype selective alpha2A agonists. Chimeric receptor were constructed to replace defined TMDs of the wild-type human alpha2A adrenoceptor with homologous sequence from the human beta2 adrenoceptor which itself has no affinity for DEX.
Chimerae of the human alpha2A and human beta2 adrenoceptors were constructed from genes encoding human alpha2A (or C10) and beta adrenoceptors. COS-7 cells were transfected with 12 new constructs as well as the wild-type human alpha2A and human beta2 adrenoceptors. Cells were harvested and membranes prepared for radiolabeled ligand binding using 3H-atipamezole and DEX as the displacing ligand.
TMD#7 is pivotal for DEX binding since CRS 25 (alpha2 TMD#7) has > 10,000 for higher affinity than CRT3 (beta2 TMD#7). To a lesser extent TMD#2 is involved in DEX binding since CRS16 (alpha2 TMD#2) has >100 fold higher affinity for DEX than does beta2 adrenoceptor. TMD#6 may be involved in DEX binding since CRS 25(alpha2 TMD#6) has 10 fold higher affinity for DEX than does CR8 (beta2 TMD#6).
The next generation of alpha2 adrenergic agonists needs to be alpha2A subtype selective. To better understand the amino acid residues responsible for subtype selectivity, further site-directed mutagenesis studies of the differences in amino acid residues in TMD#7 and 2 (and 6) between the three adrenoceptor subtypes need to be undertaken. This will facilitate target-based drug design of the novel alpha2A subtype selective agonists for use in anesthesia.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] 溝部俊樹: "アドレナリン受容体とα2作動薬 1.アドレナリン受容体の分子薬理学"麻酔. 46(5). 650-657 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 溝部俊樹: "アドレナリン受容体とα2作動薬 2.アドレナリン受容体の構造と機能"麻酔. 46(6). 770-776 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 溝部俊樹: "アドレナリン受容体とα2作動薬 3.ノックアウトマウスとノックダウンラットによる受容体サブタイプの機能解析"麻酔. 46(7). 934-941 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 溝部俊樹: "アドレナリン受容体とα2作動薬 4.α2作動薬の臨床薬理学"麻酔. 46(8). 1066-1070 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Toshiki Mizobe: "Molecular Genetic technology defines the receptur subtypes responsible rof anesthetic and cardiovacular responses to α2 adrenergic agonists"Circulation Control. 19. 89-95 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M.Mase, T.Mizobe et al: "α2-adrenergic receptors : structure, function and therapeulic inplications"harwood academic puglishers. 193 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mizobe T: "Where does dexmedetomidine bind on the alpha2 adrenergic receptor ?"Anesthesiology. 87. A701

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Maze M, Buttermann A E, Kamibayashi T, Mizobe T: "Alpha-2 adrenergic agonists"Textbook of Intravenous Anethesia, Williams & Wilkins, Baltimore. 433-445 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mizobe T: "Adrenergic receptors and alpha2 agonists ; 1) Molecular biological study of adrenoceptors"Masui. 46(5). 650-657 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mizobe T: "Adrenergic receptors and alpha2 agonists ; 2) Structure-function relationship of adrenoceptors"Masui. 46(6). 770-776 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mizobe T: "Adrenergic receptors and alpha2 agonists : 3) Function analysis of adrenoceptor subtype by knockout mice and knockdown rats"Masui. 46(7). 934-941 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mizobe T: "Adrenergic receptors and alpha2 agonists ; 4) Applied and clinical pharmacology of alpha2 agonist"Masui. 46(8). 1066-1070 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mizobe T, Kamibayashi T, Tianzhi G, Harasawa K. Maze M: "Molecular genetic technology defines the receptor subtypes responsible for anesthetic and cardiovascular responses to alpha2 adrenergic agonists"Circ Cont. 19. 89-95 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Maze M, Mizobe T: "Clinical applications of Alpha2 adrenergic agonists in the perioperative period : Neurobiologic considerations. In : Lanier SM, Limbird LE, editors. Alpha2 adrenergic receptors ; structure, function and therapeutic implications."Ameterdam : Harwood Academic Publishers. 161-170 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Toshiki Mizobe: "Haematological Effects of Anaesthetics and Anaesthesia"Current Opinion in Anaesthesiology. 12. 437-441 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Toshiki Mizobe: "Molecular Genetic Technology Defines the Receptor Subtypes Reponsible for Anesthetic and Cardrovascular Responses to alpha-2 Adrenergic Agonists." Circulation Control. 19. 89-95 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Meroyn Maze: "α_2-Adrenergic Receptors:structure,function and Therapentic Implications." harwood academic publishers, 193 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 溝部俊樹: "アドレナリン受容体とα_2作動薬 1:アドレナリン受容体の分子薬性学" 麻酔. 46・5. 650-657 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 溝部俊樹: "アドレナリン受容体とα_2作動薬 2:アドレナリン受容体の構造と機能" 麻酔. 46・6. 770-776 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 溝部俊樹: "アドレナリン受容体とα_2作動薬 3:ノックアウトマウスとノックダウンラットによる受容体サブタイプの機能解析" 麻酔. 46・7. 934-941 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 溝部俊樹: "アドレナリン受容体とα_2作動薬 4:α_2作動薬の臨床薬性学"

    • Related Report
      1997 Annual Research Report
  • [Publications] Toshiki Mizobe, et al.: "Where does dexmedetomidine bind on the α_2 adreno ceptor?" Anesthesiology. V87・3A. A701 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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