Shaltiel Galit, Mark Shirley, Kofman Ora, Belmaker Robert H, Agam Galila
Stanley Research Center, Ben-Gurion University of the Negev, PO Box 4600, Beersheva 84170, Israel.
Pharmacol Rep. 2007 Jul-Aug;59(4):402-7.
We have recently shown that valproate (VPA) decreases intracellular concentrations of inositol, like lithium but via a different mechanism, namely by inhibiting myo-inositol-1-phosphate (MIP) synthase. Valnoctamide (VCD) and valrocemide (VGD) are VPA derivatives which are anticonvulsants and have been shown in animal models to be significantly less teratogenic than VPA. We now show that 1 mM of either VCD or VGD drastically inhibits human brain crude homogenate MIP synthase activity. We studied the mechanism of the effect of VCD and found that it reduced the enzyme activity by an apparent competitive mode of inhibition at concentrations within the therapeutic range of VPA(Ki = 0.18 mM). We studied the behavioral effect of VGD and found that both lithium and VGD attenuated amphetamine-induced increase in rearing. These data support clinical study of these VPA-derivatives in bipolar disorder.
我们最近发现，丙戊酸盐（VPA）会降低细胞内肌醇的浓度，这与锂盐类似，但作用机制不同，即通过抑制肌醇-1-磷酸（MIP）合酶来实现。缬草酰胺（VCD）和缬草西胺（VGD）是VPA的衍生物，它们是抗惊厥药，并且在动物模型中已显示出比VPA的致畸性明显更低。我们现在表明，1 mM的VCD或VGD会显著抑制人脑粗匀浆中的MIP合酶活性。我们研究了VCD的作用机制，发现它在VPA治疗范围内的浓度下通过明显的竞争性抑制模式降低了酶活性（Ki = 0.18 mM）。我们研究了VGD的行为效应，发现锂盐和VGD均减弱了苯丙胺诱导的竖毛增加。这些数据支持对这些VPA衍生物用于双相情感障碍的临床研究。
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