HMN-709, a Chlorobenzenesulfonamide Derivative, Is a New Membrane-Permeable Calmodulin Antagonist.

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  • Yokokura Hisayuki
    <I>The Department of Pharmacology, Nagoya University School of Medicine</I>
  • Okada Yohei
    <I>The Department of Pharmacology, Nagoya University School of Medicine</I>
  • Terada Osamu
    <I>The Department of Pharmacology, Nagoya University School of Medicine</I>
  • Hidaka Hiroyoshi
    <I>The Department of Pharmacology, Nagoya University School of Medicine</I>

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タイトル別名
  • HMN-709 a Chlorobenzenesulfonamide Deri

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説明

Our objective is to describe the basic chemical and biological properties of the new calmodulin antagonist HMN-709 (2-[N-(2-aminoethyl)-N-(4-chlorobenzenesulfonyl)]amino-N-(4-fluorocinnamyl)-N-methylbenzylamine). This newly synthesized compound was found to inhibit the Ca2+/calmodulin-dependent activation of calmodulin kinase I, smooth muscle myosin light chain kinase and Ca2+-phosphodiesterase with IC50 Values of 1.57±0.21, 2.29±0.09 and 0.30±0.08 μM (mean±S.E.), respectively. This compound showed little or no effect on the Ca2+/calmodulin-independent activation of protein kinase A, protein kinase C and basal phosphodiesterase. In addition, HMN-709 inhibited calmodulin kinase I competitively with respect to calmodulin (Ki=0.88 μM) and non-competitively with respect to ATP. Affinity chromatography, with HMN-709-coupled Sepharose HP, showed that the compound bound to calmodulin in a Ca2+-dependent manner and did not bind to calmodulin kinase I. These results suggest that HMN-709 antagonizes calmodulin by binding to Ca2+/calmodulin. HMN-709 inhibited collagen-induced platelet aggregation with an IC50 value of 11.80±0.86 μM (mean±S.E.) without inhibiting phorbol 12, 13-dibutyrate-induced aggregation at doses up to 12 μM. HMN-709 appears to be a new, membrane-permeable calmodulin antagonist that may be used for studying the involvement of calmodulin in cellular processes.

収録刊行物

  • Jpn.J.Pharmacol.

    Jpn.J.Pharmacol. 72 (2), 127-135, 1996

    公益社団法人 日本薬理学会

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