• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Development of the 4th generation calcium antagonists based on molecular revealing the binding sites in calcium channels

Research Project

Project/Area Number 08557138
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 医薬分子機能学
Research InstitutionKumamoto University

Principal Investigator

NAKAYAMA Hitoshi  Kumamoto University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (70088863)

Co-Investigator(Kenkyū-buntansha) NABATA Hiroyuki  Chugai Pharmaceutical Co., LTD., Laboratory of Cardiovascular Diseases, Head, 創薬研究所, 所長
豊島 近  東京大学, 分子細胞生物学研究所, 教授 (70172210)
KUNIYASU Akihiko  Kumamoto University, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 教務員 (90241348)
KAWANO Seiko  Tokyo Medical and Dental University, Medical Research Institute, Associate Profe, 難治疾患研究所, 助教授 (00177718)
ISHIZUKA Tadao  Kumamoto University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (60176203)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 1998: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥3,200,000 (Direct Cost: ¥3,200,000)
KeywordsCalcium antagonist / photoaffinity labeling / drug binding site / structural biology / new compounds / drug design / 光アフィニティラベリング / 心筋Caチャンネル / 精密合成化学 / 抗ペプチド抗体 / 薬理活性
Research Abstract

In this project, we aim to reveal binding sites for calcium antagonists in cardiac calcium channels by photoaffinity labeling and the results are to be applied to design and synthesis of new drugs. New findings are as follows. (1) We identified the dihydropyridine 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 in two calcium channels. (2) 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. (3) We revealed the binding site of a new typed calcium antagonist of 1, 4-benzothiazine structure I which is homologous to benzothiazepine 2 but the identified sites were different. The results can explain the pharmacological difference between two drugs. (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.

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] H.Nakayama A.Kuniyasu: "Identification of the binding sifes For calcium channel antagonists" Jpn.Heart J.37. 643-650 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.Akao,et al.: "Myocardial ischemia induces differential regulation of KATP channel gene expression in rat heart." J.Clin.Invest.100. 3053-3059 (1997)

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

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.Ohkura,et al.: "Dual regulation of the skeletal muscle ryanodine receptors by triadin and calsequestrin." Biochemistry. 37. 12987-12993 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] N.Ii,et al.: "Photochemical Cocalization of the semotiadil binding region with cardiac Ca^<2+> channel α1 subunit." FEBS Letters. 441. 83-87 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] A.Kuniyasu, et al.: "A new scorpion toxin which stimulates the Ca^<2+>-release channel activity of the skeletal muscle ryansdine receptor." Biochem. J.339(in press.). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [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
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Nakayama and A.Kuniyasu: "Identification of the binding sites for calcium channel antagonists" Jpn.Heart J.37. 643-650 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.Akao, A.Kuniyasu, H.Nakayama, et al. (6): "Myocardial ischemia induces differential regulation of K_<ATP> channel gene expression." J.Clin.Invest.100. 3053-3059 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] A.Kuniyasu, A.Schwartz, H.Nakayama, et al. (4): "Photochemical identification of transmembrane segment IVS6 as the binding region of a semotiadil, a new calcium modulator for the L-type 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
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.Ohkura, H.Nakayama, Y.Ohizumi, et al. (7): "Dual regulation of the skeletal nuscle ryanodine receptor by triadin and calsequestrin." Biochemistry. 37. 12987-12993 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] N.Ii, A.Kuniyasu, H.Nakayama, et al. (3): "Photochemical localization of the semotiadil binding region within cardiac Ca^<2+> channel alpha1 subunit. Comparison with the skeletal muscle counterpart." FEBS Letters. 441. 83-87 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] A.Kuniyasu, S.Kawano, H.Nakayama, et al. (7): "A new scorpion toxin which stimulates the Ca^<2+> release channel activity of the skeletal muscle ryanodine receptor by an indirect mechanism." Biochem.J.339 (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] A.Kuniyasu,et al.: "Photochemical identification of transmembrane segment TVS6 as the binding region of semotiadil for the Ca^<2+> channeL." J.Biol.Chem.273. 4635-4641 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.Anzai,et al.: "Effects of hydroxyl radical and sulfhydryl reagents on the open probability of the purified cardiac ryanodine receptor." Biochem.Biophys.Res.Commun.249. 938-942 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] M.Ohkura,etal.: "Dual regulation of the sheletal muscle ryanodine receptors by triadin and calsequestrin." Biochemistry. 37. 12987-12993 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] N.Ii,et al.: "Photochemical localization of the semotiadil binding region wethin cardiac Ca^<2+> channel αl subnit." FEBS Letters. 441. 83-87 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] L-C. Xu,et al.: "Bis(hydroyamide)-based bi functional chelating agent for 99m TC Labeling of polypeptides." Bioconjugate Chem.10. 9-17 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] A.Kuniyasu,et al.: "A new scorpion toxin which stimulates the Ca^<2+> release channel activity of the skeletal muscle ryanodine receptor." Biochem.J.339(in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] M. Akao, et al.: "Myocardial ischemia induces differential regution of K_<ATP> channel gene expression in rat hearts" J. Clin. Invest.100. 3053-3059 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] S. Takeda, et al.: "Adenosine 5'-triphosphate binding to bovine serum albumin" Biophys. Chem.70. 175-183 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] M. Nakayama, et al.: "Hydroxamide as a cherating molety for the preparation of ^<99m>Tc-radiopharmaceuticals. III." Appl. Radiat. Isot.48. 571-577 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] L. -C. Xu, et al.: "Synthesis and evalution of hydroxamide-based tetradendate Ligands as a new class of thiol-free chelating molecules" Nucl. Med. Biol.25(印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] A. Kuniyasu, et al.: "Photochemical identification of transmembrane segment IVS6 as a binding region of semotiadil" J. Biol. Chem.273. 4635-4641 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 國安明彦ら: "Caチャンネルの分子構造と機能相関" 心臓. 30. 71-76 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 中山仁: "医系薬理学(遠藤仁, 橋本敬太郎, 後藤勝年・偏著)" 中外医学社, 562 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Hatanaka,et al.: "Diazirine-based photoaffinity labeling : Chemical approach to biological interfaces" Rev.Heteroatom Chem.14. 213-243 (1996)

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

    • Related Report
      1996 Annual Research Report
  • [Publications] A.Kuniyasu,et al.: "Identification of the 1,4-dihydropyridine binding sites within the α1 subunit of the cardiac calcium channels" Eur.J.Biochem.(印刷中). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] A.Kuniyasu,et al.: "Identification of the binding region for a new calcium antagonist within the α1 subunit of calcium channels" J.Biol.Chem.(印刷中). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] H.Yabana,et al.: "Identification of the benzothiazepine binding sites within the α1 subunt of calcium channel by photpaffinity Labeling" J.Biol.Chem.(印刷中). (1997)

    • Related Report
      1996 Annual Research Report

URL: 

Published: 1997-04-01   Modified: 2021-08-20  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi