DY-9760e, a novel calmodulin antagonist with cytoprotective action

Masunobu Sugimura, Toshiyuki Sato, Wakako Nakayama, Yoshiyuki Morishima, Koji Fukunaga, Masao Omitsu, Eishichi Miyamoto, Yasufumi Shirasaki

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

We report the pharmacological characterization and cytoprotective effect of DY-9760e, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4 -imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, a novel antagonist of calmodulin. DY-9760e inhibited calmodulin-dependent enzymes, including calmodulin-dependent phosphodiesterase and myosin light chain kinase with K(i) values of 1.4, 12, 2.0, 3.8 and 133 μM, respectively. These antagonistic effects of DY-9760e were more potent than these of W-7, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, another calmodulin antagonist. This compound showed little or no effect on calmodulin-independent enzymes, such as protein kinase A and C and calpain I and II. Analysis of the hydrophobic interaction of DY-9760e with calmodulin by using 2-p-toluidinylnaphthalene-6-sulfonate and 9-anthroylcholine revealed that, like W-7, DY-9760e bound to the hydrophobic regions of calmodulin. The [14C]DY-9760e binding assay indicated that DY-9760e bound to calmodulin at one class of binding site. Finally, DY-9760e substantially protected N1E-115 neuroblastoma cells from cytotoxicity induced by the Ca2+ ionophore, A23187. These results indicate that DY-9760e, a novel calmodulin antagonist, possesses a cytoprotective action and suggest that calmodulin plays a critical role in mediating some of the biochemical events leading to cell death following Ca2+ overload.

Original languageEnglish
Pages (from-to)99-106
Number of pages8
JournalEuropean Journal of Pharmacology
Volume336
Issue number1
DOIs
Publication statusPublished - 1997 Oct 1
Externally publishedYes

Keywords

  • Calmodulin antagonist
  • Cytotoxicity
  • DY-9760e
  • Neuroprotection
  • W7

ASJC Scopus subject areas

  • Pharmacology

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