Novel Pharmacological Protiles of Dihydropyridines

二氢吡啶的新药理特征

• 批准号: 15590071
• 负责人: TANAKA Hikaru
• 金额: $ 1.86万
• 依托单位: Toho University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590071/
• 关键词: dihydropyridines; T-type Ca^<2+> channel; Cl^- channel; ischemia-reperfusion; heart; ジドロピリジン; クロライドチャネル; ジヒドロピリジン化合物; 徐脈; 虚血再灌流傷

Pharmacology of dihydropyridine compounds with blocking activity on ion channels other than the L-type Ca^<2+> channel was studied. T-type Ca^<2+> channel blockade is now receiving attention as a novel therapeutic strategy for various cardiovascular disorders. A specific T-type Ca^<2+> channel blocker has not yet been established. We found that certain dihydropyridine compounds, such as efonidipine, have blocking activity on both L-type and T-type Ca^<2+> channels which possibly underlies their excellent clinical profiles such as minimum reflex tachycardia and renal protection. A phosphonate moiety or some bulky structure at the C5 position of the dihydropyridine ring may be important for the T-type Ca^<2+> channel blocking activity. AHC-52 and PAK200 are dihydropyridine compounds which block the cAMP-dependent chloride channel but not L-type Ca^<2+> channel. These compound were shown to enhance recovery of myocardial contractile force after ishcemia -reperfusion. A remarcable feature of this cardioprotection is that it was not accompanied by cardiosuppression. These compounds were found to attenuate the decrease in cellular ATP through protection of mitochondrial function. Thus, precise pharmacological investigation of dihydropyridine compounds with blocking activity on ion channels other than the L-type Ca^<2+> channel would lead to the development of cardioprotective agents acting through novel mechanisms.

研究了对L-型Ca 2+ 通道以外的离子通道具有阻断活性的二氢吡啶化合物的药理学。 T型Ca 2+ 通道阻断作为多种心血管疾病的新治疗策略目前受到关注。尚未建立特定的T型Ca 2+ 通道阻断剂。我们发现某些二氢吡啶化合物，例如依福地平，对L型和T型Ca 2+ 通道均具有阻断活性，这可能是其优异的临床特征（例如最小反射性心动过速和肾脏保护）的基础。二氢吡啶环的C5位置处的膦酸酯部分或一些大的结构对于T型Ca 2+ 通道阻断活性可能是重要的。 AHC-52和PAK200是二氢吡啶化合物，其阻断cAMP依赖性氯离子通道但不阻断L-型Ca 2+ 通道。这些化合物显示出增强缺血再灌注后心肌收缩力的恢复。这种心脏保护的一个显着特点是它不伴随心脏抑制。这些化合物被发现可以通过保护线粒体功能来减弱细胞 ATP 的减少。因此，对除L型Ca 2+ 通道之外的离子通道具有阻断活性的二氢吡啶化合物的精确药理学研究将导致通过新机制发挥作用的心脏保护剂的开发。

项目成果

Masumiya H., Saito M., Ito M., Matsuda T., Noguchi K., Iida-Tanaka N., Tanaka H., Shigenobu K.: "Lack of action potential-prolonging effect of terfenadine on rabbit myocardial preparations"Biol.Pharmaceut.Bull.. 27. 131-135 (2004)

Masumiya H.、Saito M.、Ito M.、Matsuda T.、Noguchi K.、Iida-Tanaka N.、Tanaka H.、Shigenobu K.：“特非那定对兔心肌制剂缺乏动作电位延长作用”Biol

The R(-)-Enantiomer of Efonidipine Blocks T-type but Not L-type Calcium Current in Guinea Pig Ventricular Myocardium

埃福地平 R(-)-对映体阻断豚鼠心室心肌 T 型钙电流，但不阻断 L 型钙电流

• 发表时间: 2004
• 期刊: Journal of Pharmacological Sciences 96
• 作者: 田中 光

Atrio-ventricular difference in myocardial excitation-contraction coupling

心肌兴奋-收缩耦合的房室差异

• 发表时间: 2003
• 期刊: Journal of Pharmacological Sciences 93
• 作者: 田中 光;武田 健太郎;田中 光
• 通讯作者: 田中 光

Nishimaru K., Tanaka Y., Tanaka H., Shigenobu K: "Inhibition of agonist-induced positive inotropy by a selective Rho-asociated kinase inhibitor, Y-27632"J.Pharmacol.Sci.. 92. 424-427 (2003)

Nishimaru K.、Tanaka Y.、Tanaka H.、Shigenobu K：“选择性 Rho 相关激酶抑制剂 Y-27632 对激动剂诱导的正性肌力的抑制”J.Pharmacol.Sci.. 92. 424-427 (2003

Nishimaru K., Tanaka Y., Tanaka H., Shigenobu K.: "Pharmacological evidence for involvement of phospholipase D, protein kinase C and sodium-calcium exchange in α-adrenoceptor-mediated negative inotropy in adult mouse ventricle"J.Pharmacol.Sci.. 92. 196-20

Nishimaru K.、Tanaka Y.、Tanaka H.、Shigenobu K.：“成年小鼠心室 α-肾上腺素受体介导的负性肌力中磷脂酶 D、蛋白激酶 C 和钠钙交换参与的药理学证据”J.Pharmacol。科学.. 92. 196-20