Suzuki Y, Tamura K, Adachi Y, Fukazawa M, Kato T
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Shizuoka, Japan.
Eur J Pharmacol. 1998 Jan 26;342(2-3):347-51. doi: 10.1016/s0014-2999(97)01496-9.
CP-060S, (-)-(S)-2-[3,5-bis(1,1-dimethylethyl)-4-hydroxypheny1]-3-[3-[N-met hyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thi azolidin-4-one hydrogen fumarate is a novel cardioprotective drug, which is able to prevent Na+-, Ca2+-overload and also has Ca2+ channel blocking activity. The latter action of CP-060S was characterized by radioligand binding experiments with rat cardiac membranes in terms of the interaction with the three principal binding sites on the L-type Ca2+ channel, which bind such drugs as the 1,4-dihydropyridines, phenylalkylamines and benzothiazepines. CP-060S exhibited complete and concentration-dependent inhibition of 3H-PN200-110, 3H-desmethoxyverapamil and [3H]cis-(+)-diltiazem binding to their specific binding sites. Saturation studies showed that CP-060S increased the Kd of 3H-PN200-110 and 3H-desmethoxyverapamil without causing a significant change in the maximum binding density. The dissociation kinetics of the three radioligands were accelerated by CP-060S. These results suggest that CP-060S interacts with a novel binding site on the L-type Ca2+ channel and has a negative allosteric interaction with the three principal binding sites for the 1,4-dihydropyridines, phenylalkylamines and benzothiazepines.
CP - 060S，（-）-（S）-2 - [3,5 - 双（1,1 - 二甲基乙基）-4 - 羟基苯基] - 3 - [3 - [N - 甲基 - N - [2 - （3,4 - 亚甲二氧基苯氧基）乙基]氨基]丙基] - 1,3 - 噻唑烷 - 4 - 酮富马酸氢盐是一种新型心脏保护药物，它能够防止Na⁺、Ca²⁺超载，并且还具有Ca²⁺通道阻断活性。CP - 060S的后一种作用通过用大鼠心肌膜进行放射性配体结合实验来表征，该实验涉及与L型Ca²⁺通道上的三个主要结合位点的相互作用，这些位点可结合诸如1,4 - 二氢吡啶类、苯基烷基胺类和苯并硫氮杂䓬类等药物。CP - 060S对[³H]（+）-PN200 - 110、[³H]（-）-去甲氧基维拉帕米和[³H]顺式（+）-地尔硫䓬与其特异性结合位点的结合表现出完全的浓度依赖性抑制。饱和研究表明，CP - 060S增加了[³H]（+）-PN200 - 110和[³H]（-）-去甲氧基维拉帕米的解离常数（Kd），而最大结合密度没有显著变化。CP - 060S加速了这三种放射性配体的解离动力学。这些结果表明，CP - 060S与L型Ca²⁺通道上的一个新结合位点相互作用，并且与1,4 - 二氢吡啶类、苯基烷基胺类和苯并硫氮杂䓬类的三个主要结合位点具有负变构相互作用。
