Muramatsu M, Fujita-Tominaga A, Tanaka M, Ishii Y, Aihara H
Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Jpn J Pharmacol. 1988 Dec;48(4):453-62. doi: 10.1254/jjp.48.453.
The binding to a Ca-channel of a novel 1,4-dihydropyridine (DHP) Ca-antagonist, 2-nitratopropyl 3-nitratopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (CD-349), was studied in rat myocardium and brain and hog coronary artery, and the binding was compared with that of other DHPs. In rat myocardium, the binding reaction of [3H]CD-349 was faster than that of nitrendipine (NTD). The association rate constant of [3H]CD-349 was about 10 times higher than that of [3H]NTD. The dissociation rate was also higher than that of [3H]NTD. Scatchard plot analysis of [3H]CD-349 binding showed one high affinity site for CD-349. The dissociation constant (Kd) and maximum number of binding sites (Bmax) were 333 pM and 286 fmoles/mg protein. They were almost the same as those for [3H]NTD. [3H]CD-349 and [3H]NTD bindings were dose dependently inhibited by 1,4-DHPs: nifedipine, nimodipine, nicardipine and CD-349. The order of the inhibitory potency of these drugs was CD-349 greater than nicardipine greater than nimodipine greater than nifedipine, when [3H]CD-349 and [3H]NTD were used as the ligands. Similar results were obtained for rat brain and hog coronary artery. [3H]CD-349 binding was not changed by alpha- or beta-adrenergic, cholinergic, histaminergic or serotonergic agents in rat myocardium. From these results, it is suggested that CD-349 binds to the Ca-channel reversibly with high affinity due to its high association rate for the site.
研究了新型1,4 - 二氢吡啶（DHP）钙拮抗剂2 - 硝酸丙酯3 - 硝酸丙酯2,6 - 二甲基 - 4 -（3 - 硝基苯基）-1,4 - 二氢吡啶 - 3,5 - 二羧酸酯（CD - 349）在大鼠心肌、脑以及猪冠状动脉中与钙通道的结合情况，并将该结合与其他二氢吡啶类药物进行了比较。在大鼠心肌中，[3H]CD - 349的结合反应比尼群地平（NTD）更快。[3H]CD - 349的缔合速率常数约比[3H]NTD高10倍。解离速率也高于[3H]NTD。对[3H]CD - 349结合的Scatchard图分析显示CD - 349有一个高亲和力位点。解离常数（Kd）和最大结合位点数（Bmax）分别为333 pM和286 fmol/mg蛋白。它们与[3H]NTD的几乎相同。[3H]CD - 349和[3H]NTD的结合受到1,4 - DHP类药物（硝苯地平、尼莫地平、尼卡地平和CD - 349）的剂量依赖性抑制。当以[3H]CD - 349和[3H]NTD作为配体时，这些药物的抑制效力顺序为CD - 349大于尼卡地平大于尼莫地平大于硝苯地平。在大鼠脑和猪冠状动脉中也获得了类似结果。在大鼠心肌中，α或β肾上腺素能、胆碱能、组胺能或5 - 羟色胺能药物不会改变[3H]CD - 349的结合。从这些结果表明，由于CD - 349对该位点的高缔合速率，它以高亲和力与钙通道可逆性结合。
