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1997 Fiscal Year Final Research Report Summary

Drug binding in cardiac calcium channels : Identification and its application to drug development

Research Project

Project/Area Number 08044306
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research Field 医薬分子機能学
Research InstitutionKumamoto University

Principal Investigator

NAKAYAMA Hitoshi  Kumamoto University, Facultyr of Pharmaceutical Science, Professor, 薬学部, 教授 (70088863)

Co-Investigator(Kenkyū-buntansha) DALY John W.  NIH,Laboratory of Bioorganic Chemistry, Section Chief, 生物有機化学研究部, 部長
BCHWARTZ Arnold  Cincinnati Universitu College of Medicine, Professor, Chairman, 医学部, 主任教授
KUNIYASU Akihiko  Kumamoto University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教務員 (90241348)
KUNIEDA Takehisa  Kumamoto University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (80012649)
Project Period (FY) 1996 – 1997
Keywordscalcium antagonist / photoaffinity labeling / cardiac calsium channel / drug binding site / new compounds / drug design / synthesic chemistry
Research Abstract

In this project, we aim to reveal binding sites for calcium antagonists in cardiac calcium channels by photoaffinity laveling and the results are to be applied to design and synthesis of new drugs. New findings are as follows. (1) Benzothiazepine binding sites were identified in segment 5 and 6 in repeat IV by photoaffinity labeling using azidobutyryl clentiazem with a rather small-sized photoprobe. The recent report by foreign investigaters where two labeled sites in repeat III and IV must be a wrong conclusion resulted from using a bulky photoprobe with long side chain. (2) We revealed the binding site of semotiadil, a new typed calcium antagonist of 1,4-benzothiazine structure 1^^- which is homologous to benzothiazepine 2^^- but the identified sites were different. Theidentified site by photoaffinity labeling was solely in S6 of repeat IV which was partly shared with other calcium antagonist binding sites but not overlapped completely. The results can explain the pharmacological interactions among these drugs. (3) We also identified the semotiadil sites in cardiac channel, which were identical to the skeletal muscle counterpart but some amino acids were substituted. The substitution can be interpreted to dominate the difference of binding affinity and tissue selectivity in part in two calcium channels. (4) Three dimentional structures of 1 and 2 are not ovelapped by x-ray crystallographic analysis. It suggests that we will design and synthesis of improved calcium antagonists which are derived from 2 as a lead compound.

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] H.Nakayama,et al.: "Identification of the binding sites for calcium channel antagonists." Japn.Heart J.37. 643-650 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Hatanaka,et al.: "Diazirine-based photoaffinity labeling:Chemical approach to biological interfases." Rev.Heteroatom Chem.14. 213-243 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Akao et al.: "Myocardial ischemia induces differential regulation of Kftp channel gene expession in rat hearts." J.Clin.Invest.100. 3053-3059 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Tanaka,et al.: "Adenosine 5'-triphosphate binding to bovine serum" Biophys.Chem.70. 175-183 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Nakayama,et al.: "Hydroxamide as a chalating molety for the preparation of 99mTc-radiopharmaceuticals.III." Appl.Radiat.Isot.48. 571-577 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] A.Kuniyasu,et al.: "Photochemical identification of transmembrane segment IVS6 as a binding region of semotiadil" J.Biol.Chem.273. 4635-4641 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 中山 仁: "医系薬理学(遠藤 仁,橋本 敬太郎,後藤 勝年・編著)" 中外医学社, 562 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Hatanaka, et al.: "Diazirine-based photoaffinity labeling : Chemical approach to biological interfaces." Rev.Heteroatom Chem. 14. 213-243 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] H.Nakayama and A.Kuniyasu: "Identification of the binding sites for calcium channel antagonists" Japn.Heart J.37. 643-650 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Nakayama, et al.: "Hydrozamide as a chelating moiety for the preparation of ^<99m>Tc-radiopharmaceuticals.III." Appl.Radiat.Isot.48. 571-577 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Akao, et al.: "Myocardial ischemia induces differential regulation of KATP channel gene expression in rat hearts." J.Clin.Invest.100. 3053-3059 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S.Takeda, et al.: "Adenosine 5'-triphosphate binding to bovine serum albumin." Biophys.Chem.70. 175-183 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] A.Kuniyasu, et al.: "Photochemical identification of transmembrane segment IVS6 as the binding region of semotiadil, a new modulator for the voltage dependent Ca^<2+> channel." J.Biol.Chem.273. 4635-4641 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] L.-C.Xu, et al.: "Synthesis and evaluation of hydroxamide-based tetradentate ligands as a new class of thiol-free chelating molecules for ^<99m>Tc-radiopharmaceuticals." Nucl.Med.Biol.25 (in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-16  

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