CHEMICAL STRUCTURE OF HYPOTHALAMIC NA/K ATPASE INHIBITOR

下丘脑 NA/K ATP 酶抑制剂的化学结构

• 批准号: 2229582
• 负责人: Garner Tripp Haupert
• 金额: $ 41.79万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2229582
• 关键词: cardiac glycoside aglycone; chemical structure function; circular dichroism; hypothalamic hormones; liquid chromatography; mass spectrometry; ouabain; phosphatase inhibitor; sodium potassium exchanging ATPase

Recent experiments suggest that there might be an endogenous mammalian analogue to the digitalis glycosides which would regulate the mammalian Na+/K+-ATPase (Na+ pump) in a physiologic rather than pharmacologic way. Such a compound has been linked to control of renal Na+ excretion, positive inotropic effects in cardiac muscle, and may play a role in the pathogenesis of a prevalent human disease, hypertension. A high affinity, specific, reversible inhibitor of the mammalian Na+/K+-ATPase has been completely purified from bovine hypothalamus. This hypothalamic inhibitory factor, HIF, has biological properties similar to, but not identical to, those of the cardiac glycoside, ouabain, and consistent with physiologic regulation in vivo. Physiochemical characterization of HIF indicates that while both ouabain and HIF are found to be alpha-L rhamnosides, they are structurally different in their aglycone portions. This structural difference is presumed to account for the observed differences in the biological properties of HIF and ouabain. The aims of the current proposal are (1) to purify several micrograms of HIF, utilizing established procedures; (2) to use the pure HIF to determine by liquid chromatography/mass spectrometry and circular dichroism spectrometry whether the aglycones of ouabain and HIF are stereochemically identical; (3) if they are not identical, to use further spectroscopic studies to assign the sterochemistry of the HIF-aglycone; and (4) if they are identical, to synthesize position isomers testing the products for biological activity. Success in this work would define the specific structural difference between the pharmacologic inhibitor, ouabain, and the putative mammalian physiologic analogue, HIF. Knowing the exact structure of HIF is desirable since it would probably reveal a general strategy for improving the therapeutic index of cardiac glycosides, and provide a probe to study the proposed role of endogenous Na+/K+-ATPase inhibition in the pathogenesis of human hypertensive disease.

最近的实验表明，可能有一种内源性哺乳动物 类似于洋地黄苷，可以调节哺乳动物 Na+/K+-ATP酶（Na+泵）的生理作用而非药理作用。 这种化合物与控制肾Na+排泄有关， 在心肌中具有正性肌力作用，并可能在 高血压是一种普遍存在的人类疾病。 高 哺乳动物Na+/K+-ATP酶的亲和、特异、可逆抑制剂 已经完全从牛的下丘脑中纯化出来。 这个下丘脑 抑制因子HIF具有类似于，但不是 与强心苷、哇巴因相同， 在体内进行生理调节。 理化特性 HIF表明，虽然哇巴因和HIF都被发现是α-L 在鼠李糖苷中，它们的糖苷配基部分在结构上不同。 这种结构差异被认为是观察到的 HIF和哇巴因的生物学特性的差异。 目标 目前的建议是（1）纯化几微克的HIF， 利用已建立的程序;（2）使用纯HIF来确定 通过液相色谱/质谱和圆二色性 光谱法测定哇巴因和HIF的糖苷配基是否 （3）如果它们不相同，则进一步使用 光谱研究，以分配HIF-糖苷配基的立体化学; 和（4）如果它们是相同的，则合成位置异构体， 生物活性的产品。 这项工作的成功将决定 药理学抑制剂之间的特定结构差异， 哇巴因和假定的哺乳动物生理类似物HIF。知道 HIF确切结构是所需的，因为它可能揭示 提高心脏病治疗指数的一般策略 糖苷，并提供了一个探针，研究内源性的作用， Na ~+/K ~+-ATP酶抑制在高血压发病中的作用 疾病