Nozawa Y, Miyake H, Yamada S, Uchida S, Ohkura T, Kimura R
Pharmacology Research Laboratory, Taiho Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima 771-01, Japan.
Eur J Pharmacol. 1995 Dec 12;287(2):191-6. doi: 10.1016/0014-2999(95)00651-6.
MPC-1304, (+/-)-methyl 2-oxopropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarbonate , is a novel 1,4-dihydropyridine Ca2+ channel antagonist with potent and long-lasting antihypertensive effects. We characterized the ex vivo and in vivo binding properties of MPC-1304 to Ca2+ channel antagonist receptors in myocardial, aortic and brain tissues of spontaneously hypertensive rats (SHR) by radioreceptor assay using 3H-PN 200-110 (5-methyl-3H-PN 200-110 (4-(2,1,3-benzoxadiazol-4-yl)-1,4,-dihydro-5-methoxycarbonyl-2,6-d imethyl-1,4-dihydro-3-isopropylcarbonylpyridine-5-carboxylic acid methyl ester)). At 1 and 6 h after oral administration of MPC-1304 (10 mg/kg) in SHR, there was significant decrease (48%) in the number of 3H-PN 200-110 binding sites (Bmax) in myocardial membranes compared to control values. The plasma concentration of MPC-1304 in SHR correlated significantly with the occupation by this drug of myocardial Ca2+ channel antagonist receptors. The in vivo specific binding of 3H-PN 200-110 in particulate fractions of aorta of SHR was significantly reduced (74.8 and 37.9%, respectively) at 1 and 6 after oral administration of MPC-1304 (3 mg/kg), while the myocardial 3H-PN 200-110 binding was decreased only at 1 h later. In these rats, there was little change in cerebral cortical 3H-PN 200-110 binding. In conclusion, MPC-1304 exerted more selective and sustained occupation in vivo of Ca2+ channel antagonist receptors in vascular tissues of SHR than in those of myocardial and brain tissues.
MPC - 1304，（±）-2 - 氧代丙基甲基1,4 - 二氢 - 2,6 - 二甲基 - 4 - （2 - 硝基苯基）-3,5 - 吡啶二羧酸酯，是一种新型的1,4 - 二氢吡啶类钙离子通道拮抗剂，具有强效且持久的降压作用。我们通过使用³H-PN 200 - 110（5 - 甲基 - ³H-PN 200 - 110（4 - （2,1,3 - 苯并恶二唑 - 4 - 基）-1,4 - 二氢 - 5 - 甲氧基羰基 - 2,6 - 二甲基 - 1,4 - 二氢 - 3 - 异丙基羰基吡啶 - 5 - 羧酸甲酯））的放射受体分析法，对自发性高血压大鼠（SHR）心肌、主动脉和脑组织中MPC - 1304与钙离子通道拮抗剂受体的体外和体内结合特性进行了表征。在SHR口服MPC - 1304（10mg/kg）后1小时和6小时，心肌膜中³H-PN 200 - 110结合位点（Bmax）的数量与对照值相比显著下降（48%）。SHR中MPC - 1304的血浆浓度与该药物对心肌钙离子通道拮抗剂受体的占有率显著相关。在口服MPC - 1304（3mg/kg）后1小时和6小时，SHR主动脉微粒体部分中³H-PN 200 - 110的体内特异性结合显著降低（分别为74.8%和37.9%），而心肌中³H-PN 200 - 110结合仅在1小时后下降。在这些大鼠中，大脑皮质中³H-PN 200 - 110结合几乎没有变化。总之，与心肌和脑组织相比，MPC - 1304在体内对SHR血管组织中的钙离子通道拮抗剂受体具有更具选择性和持续性的占据作用。
