Nayler W G, Gu X H
Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria.
J Hum Hypertens. 1991 Aug;5 Suppl 1:55-9.
Amlodipine is a 'second generation', long-acting calcium antagonist. To characterise the binding properties of this drug saturation binding studies were undertaken using (-)[3H]amlodipine and rat cardiac membrane fragments. (-)[3H]Amlodipine bound to a single population of high affinity binding sites with a KD of 1.64 +/- 0.17 nM, a Bmax of 0.45 +/- 0.08 pmol/mg protein and a Hill coefficient approaching unity. Binding was slow and required up to 5 hours to reach asymptote during incubation at 25 degrees C. The specific binding was totally inhibited by (-)amlodipine and (-)D600 and partially inhibited by (+)PN200-110, Bay K8644, (+)D600 and d-cis diltiazem. These results indicate that (-)[3H]amlodipine interacts strongly with the phenylalkylamine as well as the dihydropyridine binding sites. It also interacts with the benzothiazepine binding sites. The inhibition of (-)[3H]amlodipine binding by D600 is stereospecific, (-) greater than (+)D600. Bound (-)[3H]amlodipine dissociated slowly from its binding sites, less than 40% dissociation occurring during 5 hours of incubation (k-1 = 1.53 x 10(-3) min-1). These results indicate that the binding profile of amlodipine differs from that of other dihydropyridine-based Ca2+ antagonists. In addition they explain its slow onset of action, and slowed recovery on withdrawal.
氨氯地平是一种“第二代”长效钙拮抗剂。为了表征该药物的结合特性，使用（-）[3H]氨氯地平和大鼠心脏膜片段进行了饱和结合研究。（-）[3H]氨氯地平与单一群体的高亲和力结合位点结合，KD为1.64±0.17 nM，Bmax为0.45±0.08 pmol/mg蛋白质，希尔系数接近1。结合缓慢，在25℃孵育期间需要长达5小时才能达到渐近线。特异性结合被（-）氨氯地平和（-）D600完全抑制，被（+）PN200-110、Bay K8644、（+）D600和d-顺式地尔硫卓部分抑制。这些结果表明，（-）[3H]氨氯地平与苯烷基胺以及二氢吡啶结合位点强烈相互作用。它还与苯并硫氮杂卓结合位点相互作用。D600对（-）[3H]氨氯地平结合的抑制具有立体特异性，（-）大于（+）D600。结合的（-）[3H]氨氯地平从其结合位点缓慢解离，在5小时孵育期间解离少于40%（k-1 = 1.53 x 10（-3）min-1）。这些结果表明，氨氯地平的结合谱与其他基于二氢吡啶的Ca2+拮抗剂不同。此外，它们解释了其起效缓慢以及停药后恢复缓慢的原因。
