APPROACHES TO NATRIURETIC AND ANTIHYPERTENSIVE AGENTS

利尿钠和抗高血压药物的治疗方法

• 批准号: 2487342
• 负责人: WILLIAM J WECHTER
• 金额: $ 42.08万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-20 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2487342
• 关键词: affinity labeling; animal tissue; antihypertensive agents; bioassay; drug design /synthesis /production; drug receptors; drug screening /evaluation; glomerular filtration rate; high performance liquid chromatography; kidney cell; laboratory rat; mass spectrometry; nuclear magnetic resonance spectroscopy; potassium channel; receptor binding; saluretic; spontaneous hypertensive rat; tissue /cell culture; tocopherols; urine

DESCRIPTION: The goal of our program is the mechanistic understanding of the pharmacologic control of extracellular fluid volume in humans. Toward this end the investigators have been isolating, identifying and synthesizing endogenous natriuretic factors derived from normal, uremic and congestive heart failure human urine. This application is an effort to capitalize on our recent identification and synthesis of three such factors LLU-alpha, LLU-beta1 and LLU-gamma. The most intriguing of these, LLU-alpha, is a metabolite of gamma-tocopherol. Employing these leads we hope to develop the "ideal" eukaliuretic natriuretic-antihypertensive agent via two approaches, namely: 1) the judicious application of bio-analog synthesis in order to maximize, toward the ideal, the pharmacological properties of our lead compounds and 2) the conversion of our most potent eukaliuretic/natriuretic agent (s) to a high affinity, radiolabelled, photoaffinity substrate. This compounds (s) will then be employed to identify the "natriuretic receptors." Based on the very high potency of LLU-alpha inhibiting the 70 pS K+ channel of TAL cells of the loop of Henle, it is now known where this receptor resides. Identification of, and cloning of this receptor will provide a more efficient manner in which to screen libraries of synthetic compounds (employing combinatorial chemistry in part) via development of an assay based upon the receptor-ligand interaction. Identification of the receptor will also allow us to explore the mechanism of action of this class of agents and their effects on ECF homeostasis. This two pronged approach of in vivo bioassays, in conjunction with screening against the 70 pS K+ channel and ultimately receptor based studies of synthetic bio-analog libraries, would thus expedite the search for the "ideal agent" for the treatment of salt retentive and hypertensive diseases. The successful accomplishment of this research, namely the synthesis of new eukaliuretic natriuretic-antihypertensive agents and the identification of the natriuretic receptor, would be of great significance to the treatment of cardiovascular disease and perhaps provide a mechanism of action for the vitamin E complex.

描述：我们计划的目标是机械地理解 人体细胞外液量的药理学控制。 朝向 为此，研究人员一直在分离、鉴定和合成 内源性利钠因子来源于正常、尿毒症和充血性 心力衰竭人尿。 这个应用程序是一个努力利用 我们最近鉴定和合成了三种这样的因子LLU-α， LLU β 1和LLU γ。 其中最有趣的是LLU-alpha， γ-生育酚的代谢物。 利用这些线索，我们希望 “理想”利钠利尿剂-抗高血压药物通过两个 方法，即：1）生物类似物合成的明智应用， 为了最大限度地发挥我们的药物的药理学特性， 铅化合物和2）我们最有效的转化 利钾尿/利钠尿药物的高亲和力，放射性标记， 光亲和性底物 然后将该化合物用于 确定“利钠素受体”。“基于非常高的效力， LLU-α抑制Henle袢TAL细胞的70 pS K+通道， 现在已经知道这种受体的位置。 鉴定和克隆 将提供一种更有效的方式来筛选 合成化合物库（部分采用组合化学） 通过开发基于受体-配体相互作用的测定。 受体的鉴定也将使我们能够探索其机制 这类药物的作用及其对ECF稳态的影响。 这种体内生物测定的双管齐下的方法，结合 针对70 pS K+通道进行筛选，并最终进行基于受体的研究 合成生物类似物库，因此将加快搜索 是治疗盐潴留和高血压疾病的理想药物。 这项研究的成功完成，即新的合成 利钠利尿降压药及其鉴别 利钠素受体，对治疗 心血管疾病，也许提供了一个机制， 维生素E复合物。