Ishii A, Nishida K, Oka T, Nakamizo N
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Arzneimittelforschung. 1988 Nov;38(11A):1677-80.
The in vitro receptor binding affinity of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-diyhydropyridine-3, 5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) to 3H-nitrendipine, alpha 1-adrenergic, alpha 2-adrenergic, beta-adrenergic, muscarinic cholinergic, H1-histaminergic, D2-dopaminergic, S2-serotonergic, A1 adenosine and A2 adenosine receptors was compared with that of nifedipine, nitrendipine and nicardipine. KW-3049 bound stereospecifically to 3H-nitrendipine binding sites of rat myocardium with high affinity (Ki = 0.13 nmol/l) and to the rat brain alpha 1-receptor (Ki = 1.2 mumol/l). KW-3049 exhibited no remarkable binding affinity to alpha 2, beta-, D2-, H1-, S2-, A1-, A2- and muscarinic cholinergic receptors at 100 mumol/l. KW-3049 showed competitive inhibition against 3H-nitrendipine binding when it was added simultaneously with the ligand and rat heart membranes. KW-3049 did not affect the dissociation of 3H-nitrendipine from the receptor sites. The inhibitory activity of various isomers of KW-3049 at the 3H-nitrendipine binding sites was shown in the order of S-S-(+) greater than KW-3049 (racemate, S-S-(+), R-R-(-] greater than R-R-(-) greater than S-R-(-) greater than racemate (R-S-(+), S-R-(-] greater than R-S-(+). S-S-(+)isomer was 12 times more potent than R-R-(-)isomer on Ki basis, whereas alpha 1-adrenoceptors followed the order of S-S-(+), R-S-(+), KW-3049, racemate (R-S-(+), S-R-(-], S-R-(-) and R-R-(-).
将（±）-（R*）-2,6-二甲基-4-（间硝基苯基）-1,4-二氢吡啶-3,5-二羧酸（R*）-1-苄基-3-哌啶酯甲酯盐酸盐（苯磺酸氨氯地平，KW-3049）与硝苯地平、尼群地平和尼卡地平进行比较，观察其对3H-尼群地平、α1-肾上腺素能、α2-肾上腺素能、β-肾上腺素能、毒蕈碱胆碱能、H1-组胺能、D2-多巴胺能、S2-5-羟色胺能、A1腺苷和A2腺苷受体的体外受体结合亲和力。KW-3049以高亲和力（Ki = 0.13 nmol/l）立体特异性地结合于大鼠心肌的3H-尼群地平结合位点以及大鼠脑α1受体（Ki = 1.2 μmol/l）。在100 μmol/l浓度下，KW-3049对α2、β、D2、H1、S2、A1、A2和毒蕈碱胆碱能受体无明显结合亲和力。当KW-3049与配体及大鼠心脏膜同时添加时，它对3H-尼群地平结合表现出竞争性抑制作用。KW-3049不影响3H-尼群地平从受体位点的解离。KW-3049的各种异构体在3H-尼群地平结合位点的抑制活性顺序为：S-S-（+）＞KW-3049（消旋体，S-S-（+），R-R-（-））＞R-R-（-）＞S-R-（-）＞消旋体（R-S-（+），S-R-（-））＞R-S-（+）。基于Ki值，S-S-（+）异构体的效力比R-R-（-）异构体强12倍，而α1-肾上腺素能受体的顺序为：S-S-（+）、R-S-（+）、KW-3049、消旋体（R-S-（+），S-R-（-））、S-R-（-）和R-R-（-）。
