TY - JOUR
T1 - DY-9760e, a novel calmodulin antagonist with cytoprotective action
AU - Sugimura, Masunobu
AU - Sato, Toshiyuki
AU - Nakayama, Wakako
AU - Morishima, Yoshiyuki
AU - Fukunaga, Koji
AU - Omitsu, Masao
AU - Miyamoto, Eishichi
AU - Shirasaki, Yasufumi
PY - 1997/10/1
Y1 - 1997/10/1
N2 - 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.
AB - 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.
KW - Calmodulin antagonist
KW - Cytotoxicity
KW - DY-9760e
KW - Neuroprotection
KW - W7
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UR - http://www.scopus.com/inward/citedby.url?scp=0030732695&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(97)01251-X
DO - 10.1016/S0014-2999(97)01251-X
M3 - Article
C2 - 9384259
AN - SCOPUS:0030732695
VL - 336
SP - 99
EP - 106
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1
ER -