Role of calmodulin in platelet aggregation. Structure-activity relationship of calmodulin antagonists.

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  • Author(s): Nishikawa M; Hidaka H
  • Source:
    The Journal of clinical investigation [J Clin Invest] 1982 Jun; Vol. 69 (6), pp. 1348-55.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print Cited Medium: Print ISSN: 0021-9738 (Print) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
      Original Publication: New Haven [etc.] American Society for Clinical Investigation.
    • Subject Terms:
      Calcium-Binding Proteins/*antagonists & inhibitors ; Calmodulin/*antagonists & inhibitors ; Platelet Aggregation/*drug effects; Actomyosin/metabolism ; Animals ; Binding Sites ; Binding, Competitive ; Calcium/metabolism ; Calmodulin/metabolism ; Cattle ; Chemical Phenomena ; Chemistry ; Dose-Response Relationship, Drug ; Humans ; Molecular Weight ; Phosphorylation ; Sulfonamides/metabolism
    • Abstract:
      Two series of derivatives of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), including a dechlorinated analog of W-7 (W-5) and various aminoalkyl chain analogs of W-7 (A-3, A-4, A-5, I-240, A-6) were synthesized and their structure-activity relationships with calmodulin antagonistic actions and their potencies in inhibiting human platelet aggregation in vitro were investigated. Their binding affinities to calmodulin in the presence of 100 microM Ca2+ were dependent both on the chlorination of the naphthalene ring and on the length of aminoalkyl chain. The ability of these derivatives to inhibit Ca2+-dependent phosphorylation of 20,000-dalton myosin light chain from platelets correlated well with the magnitude of their binding affinity to calmodulin. W-7(10-100 microM) inhibited in a dose-dependent manner platelet aggregation induced by collagen (2 micrograms/ml), ADP (5 microM), epinephrine (1 microgram/ml), sodium arachidonate (0.83 mM), thrombin (0.125 U/ml), and A-23187 (10 microM). The IC50 value (concentration producing 50% inhibition of aggregation) of W-7 was lower in arachidonate- and collagen-induced aggregation than in ADP- or epinephrine-induced aggregation. A good correlation between the potency in inhibition of collagen-induced aggregation by W-7 and its derivatives and their affinities to calmodulin was obtained (r = 0.94). Thus, the inhibitory mechanism of these compounds may be due to their effect on Ca2+-calmodulin-dependent processes, such as 20,000-dalton myosin light chain phosphorylation. These data also support the hypothesis that the calmodulin-mediated system has an important role in platelet function.
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    • Accession Number:
      0 (Calcium-Binding Proteins)
      0 (Calmodulin)
      0 (Sulfonamides)
      65595-90-6 (W 7)
      9013-26-7 (Actomyosin)
      SY7Q814VUP (Calcium)
    • Publication Date:
      Date Created: 19820601 Date Completed: 19820807 Latest Revision: 20190606
    • Publication Date:
      20231215
    • Accession Number:
      PMC370207
    • Accession Number:
      10.1172/jci110574
    • Accession Number:
      7085878