Structural Variants of Verapamil and W‐7 with Combined Ca2+ Entry Blockade/Myosin Phosphorylation Inhibitory Mechanisms
Structural Variants of Verapamil and W‐7 with Combined Ca2+ Entry Blockade/Myosin Phosphorylation Inhibitory Mechanisms
复制标题
具有组合 Ca2+ 进入阻断/肌球蛋白磷酸化抑制机制的维拉帕米和 W-7 的结构变体
DOI：
10.1097/00005344-198803000-00006
复制
发表时间：
1988
影响因子：
3
通讯作者：
R. Wendt
中科院分区：
文献类型：
--
作者：
P. Silver;R. Fenichel;R. Wendt
被鉴定为Wy-46，622和Wy-47，324的芳基烷基磺酰胺结合了Ca 2+进入阻滞剂维拉帕米和钙调蛋白拮抗剂W-7的联合收割机药理学特性。这些药物通过抑制肌动球蛋白中的肌球蛋白轻链（MLC）磷酸化直接抑制动脉肌动蛋白-肌球蛋白相互作用。Wy-46，622（IC 50 = 26 μM）和Wy-47，324（IC 50 = 18 μM）的效力均大于W-7（IC 50 = 35 μM）;维拉帕米在100 μM时无活性。Wy-46，622和Wy-47，324在抑制起搏兔心房中K+去极化力发展方面均不如维拉帕米有效，但比W-7有效。在抑制MLC磷酸化的较高浓度（30 μM）下，Wy-46，622和Wy-47，324在抑制完整猪冠状动脉（组胺）中受体介导的收缩方面与维拉帕米相同或更有效。5-羟色胺、前列腺素F2 a、碳环血栓烷A2）或豚鼠主动脉（白三烯C4）平滑肌。Wy-47，324（IC 50 = 16 μM）和Wy-46，622（IC 50 = 23 μM）均为肾上腺素诱导的人血小板聚集第二阶段的抑制剂; Wy-47，324比维拉帕米或W-7更有效（各自的IC 50 = 29 μM）。这些结果表明，这些药物具有组合的Ca 2+进入阻滞剂/MLC磷酸化抑制机制。此外，它们比维拉帕米更具血管特异性，并且是血管平滑肌和血小板中细胞内Ca 2+介导事件的有效抑制剂。
Arylalkylsulfonamides, identified as Wy-46,622 and Wy-47,324, combine pharmacological properties of the Ca2+ entry blocker verapamil and the calmodulin antagonist W-7. These agents directly inhibit arterial actin-myosin interactions via inhibition of myosin light chain (MLC) phosphorylation in actomyosin. Potencies of both Wy-46,622 (IC50 = 26 μM) and Wy-47,324 (IC50 = 18 μM) are greater than W-7 (IC50 = 35 μM); verapamil is inactive at 100 μM. Both Wy-46,622 and Wy-47,324 are less potent than verapamil, but more potent than W-7, at inhibiting K+ -depolarized force development in paced rabbit atria. At higher concentrations (30 μM) which inhibit MLC phosphorylation, Wy-46,622 and Wy-47,324 are either equal to or more efficacious than verapamil in inhibiting receptor-mediated contractions in intact porcine coronary (histamine. serotonin, prostaglandin F2a, carbocyclic thromboxane A2) or guinea pig aortic (leukotriene C4) smooth muscle. Both Wy-47,324 (IC50 = 16 μM) and Wy-46,622 (IC50 = 23 μM) are inhibitors of the second phase of epinephrine-induced human platelet aggregation; Wy-47,324 is more potent than verapamil or W-7 (IC50 for each = 29 μM). These results suggest that these agents possess combined Ca2+ entry blocker/MLC phosphorylation inhibitory mechanisms. Furthermore, they are more vascular specific than verapamil, and are effective inhibitors of intra-cellular Ca2+ -mediated events in vascular smooth muscle and platelets.