Stereoselectivity at the Calcium Channel: Opposite Action of the Enantiomers of a 1,4‐Dihydropyridine
Stereoselectivity at the Calcium Channel: Opposite Action of the Enantiomers of a 1,4‐Dihydropyridine
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钙通道的立体选择性：1,4-二氢吡啶对映体的相反作用
DOI：
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发表时间：
1985
影响因子：
3
通讯作者：
A. Vogel
中科院分区：
文献类型：
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作者：
R. Hof;U. Ruegg;A. Hof;A. Vogel
本文合成了新的二氢吡啶衍生物202-791 [4-（2，1，3-苯并恶二唑-4-基）-1，4-二氢-2，6-二甲基-5-硝基-3-吡啶羧酸异丙酯]的立体异构体，并在离体兔主动脉环上测定了其对去极化引起的收缩和去极化刺激的~（45）Ca ~（2+）摄取的影响。外消旋混合物在低水平去极化时增强兔主动脉环的收缩，但在高水平去极化时抑制收缩和~（45）Ca ~（2+）摄取。IC 50值分别为2.0 × 10−7和1.7 × 107 M。R对映体抑制收缩和45 Ca 2+摄取，IC 50值分别为3.2 × 10−8和4.3 × 10−8 M。该化合物未显示出刺激活性。相比之下，202-791的S对映体以几乎平行的方式使去极化诱导的收缩的浓度-反应曲线向左移动，从而增强收缩。在KCl浓度为16 mM时，该效应的EC 50值为1.8 × 10−7 M。该化合物增强45 Ca 2+摄取浓度依赖性在所有水平的去极化测试。因此，二氢吡啶衍生物的立体异构体可作为血管平滑肌上的钙进入阻断剂或钙进入增强剂，这仅取决于立体化学。如果不对称化合物引起的作用表明对钙通道具有双重作用，则应制备立体异构体。
The stereoisomers of the new dihydropyri-dine derivative 202–791 [isopropyl 4-(2,1,3-benzoxadi-azol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecar-boxylate] were synthesized separately and tested on isolated rabbit aortic rings for effects on depolarization-induced contraction and depolarization-stimulated uptake of 45Ca2+. The racemic mixture enhanced contraction of rabbit aortic rings at low levels of depolarization but inhibited contraction and 45Ca2+ uptake at high levels of depolarization. The IC50 values were 2.0 × 10−7 and 1.7 × 107 M, respectively. The R enantiomer inhibited contraction and 45Ca2+ uptake with IC50 values of 3.2 × 10−8 and 4.3 × 10−8 M, respectively. This compound showed no stimulant activity. By contrast, the S enantiomer of 202–791 shifted the concentration-response curve for depolarization-induced contraction in an almost parallel fashion to the left, thus enhancing contraction. The EC50 value for this effect at a KCl concentration of 16 mM was 1.8 × 10−7 M. This compound enhanced 45Ca2+ uptake concentration dependently at all levels of depolarization tested. Thus, the stereoisomers of a dihydropyridine derivative may behave as a calcium entry blocker or a calcium entry enhancer on vascular smooth muscle, depending only on the stereochemistry. If asymmetric compounds elicit effects suggesting a dualistic action at the calcium channel, then the stereoisomers should be prepared.