CHEMICAL STRUCTURE--HYPOTHALAMIC NA+/K+ ATPASE INHIBITOR

化学结构--下丘脑NA /K ATP酶抑制剂

• 批准号: 2029119
• 负责人: Garner Tripp Haupert
• 金额: $ 44.65万
• 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 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2029119
• 关键词: cardiac glycosides; chemical structure function; circular dichroism; enzyme inhibitors; enzyme mechanism; hypothalamic hormones; immunoaffinity chromatography; monoclonal antibody; ouabain; sodium potassium exchanging ATPase

DESCRIPTION: Hypothalamic inhibitory factor, HIF, is felt to be a mammalian analog of the digitalis glycosides with biologic and biochemical properties consistent with physiologic regulation of the mammalian sodium pump in cardiovascular, renal and nervous system tissues in vivo. Disregulation of the inhibitor-Na,K-ATPase system has been linked to the pathogenesis of human essential hypertension. Structural analysis of pure HIF showed it to be an isomer, differing in the steroid moiety, of the plant glycoside, ouabain. Recently, an ouabain-like compound (OLC) isolated from human plasma and felt to be indistinguishable from plant ouabain has been restudied and found to be different from ouabain but identical to HIF, further supporting the notion that a unique molecule may specifically regulate the human Na,K-ATPase. The simplest explanation consistent with our spectroscopic data was that HIF differed from ouabain as a position isomer rhamnoside. We synthesized eight of these peracylated analogs and obtained their CD spectra. None of them showed weak CD curves (nearly zero) which is the signature of pentanaphthoyl HIF and OLC, nor did calculated CD spectra of remaining position isomers, with the possible exception of the C5 rhamnoside. With the likelihood of a more complex difference in the steroid moiety, an affinity purification method was developed using a monoclonal anti-digoxin antibody which resulted in high yields of pure HIF, making complete structural assignment of the endogenous Na,K-ATPase inhibitor achievable. Development of monoclonal antibodies to characterize HIF and create a diagnostic assay is newly proposed.

描述：下丘脑抑制因子（Hypothalamic inhibitory factor， HIF）被认为是一种哺乳动物