Umekawa H, Yamakawa K, Nunoki K, Taira N, Tanaka T, Hidaka H
Department of Agricultural Chemistry, Mie University Faculty of Bioresources, Japan.
Biochem Pharmacol. 1988 Sep 15;37(18):3377-81. doi: 10.1016/0006-2952(88)90685-5.
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester (CV-159), a new compound synthesized from dihydropyridine, was examined for its effect on calmodulin (CaM) function. The concentration of CV-159 producing 50% inhibition of Ca2+/CaM activated myosin light chain kinase (MLC kinase) was 6.2 microM. The apparent Ki value of CV-159 was 0.8 microM for MLC kinase. On the other hand, the concentration of CV-159 producing 50% inhibition of Ca2+/CaM activated cyclic nucleotide phosphodiesterase (Ca2+-PDE) was 0.55 microM. CaM antagonized competitively the CV-159-induced inhibition of activation of both MLC kinase and Ca2+-PDE. Interaction of CV-159 with CaM was also demonstrated by fluorescence studies using dansyl-CaM (5-dimethylaminonaphthalene-1-sulfonylated CaM). CV-159 produced a decrease in fluorescence intensity of dansyl-CaM, in a Ca2+-dependent fashion, and the concentration of this drug producing 50% inhibition of dansyl-CaM fluorescence was 1.2 microM. However, the concentration of nicardipine producing 50% inhibition of MLC kinase exceeded 100 microM. CaM did not antagonize the nicardipine-induced inhibition of Ca2+-PDE. These results suggest that the action of CV-159 is unique in that it inhibits both Ca2+-PDE and MLC kinase, through interaction with calmodulin. CV-159 seems to be a different class of drug from known dihydropyridine compounds.
1,4 - 二氢 - 2,6 - 二甲基 - 4 -（3 - 硝基苯基）- 3,5 - 吡啶二羧酸甲酯6 -（5 - 苯基 - 3 - 吡唑啉氧基）己酯（CV - 159）是一种由二氢吡啶合成的新化合物，研究了其对钙调蛋白（CaM）功能的影响。对Ca2+/CaM激活的肌球蛋白轻链激酶（MLC激酶）产生50%抑制作用时CV - 159的浓度为6.2微摩尔。CV - 159对MLC激酶的表观抑制常数（Ki）值为0.8微摩尔。另一方面，对Ca2+/CaM激活的环核苷酸磷酸二酯酶（Ca2+-PDE）产生50%抑制作用时CV - 159的浓度为0.55微摩尔。CaM竞争性拮抗CV - 159对MLC激酶和Ca2+-PDE激活的抑制作用。使用丹磺酰 - CaM（5 - 二甲基氨基萘 - 1 - 磺酰化钙调蛋白）的荧光研究也证明了CV - 159与CaM的相互作用。CV - 159以Ca2+依赖的方式使丹磺酰 - CaM的荧光强度降低，产生50%抑制丹磺酰 - CaM荧光的该药物浓度为1.2微摩尔。然而，对MLC激酶产生50%抑制作用时尼卡地平的浓度超过100微摩尔。CaM不拮抗尼卡地平对Ca2+-PDE的抑制作用。这些结果表明，CV - 159的作用具有独特性，即它通过与钙调蛋白相互作用抑制Ca2+-PDE和MLC激酶。CV - 159似乎是一类与已知二氢吡啶化合物不同的药物。
