APPROACHES TO NATRIURETIC AND ANTIHYPERTENSIVE AGENTS

利尿钠和抗高血压药物的治疗方法

• 批准号: 2839029
• 负责人: WILLIAM J WECHTER
• 金额: $ 39.89万
• 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/2839029
• 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 人体细胞外液体积的药理学控制。 走向 为此，研究人员一直在分离、鉴定和合成 来自正常、尿毒症和充血性的内源性利尿钠因子 心力衰竭的人尿。 该应用程序旨在利用 我们最近鉴定和合成了三个这样的因子 LLU-alpha， LLU-beta1 和 LLU-gamma。 其中最有趣的是 LLU-alpha，它是 γ-生育酚的代谢物。 我们希望利用这些线索来发展 “理想的”利钠尿钠抗高血压药物，通过两种途径 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理特性，达到理想的效果 先导化合物和 2) 我们最有效的转化 具有高亲和力、放射性标记的真利尿剂/利尿钠剂， 光亲和底物。 然后该化合物将被用于 识别“利尿钠受体”。 基于非常高的效力 LLU-α 抑制 Henle 环 TAL 细胞的 70 pS K+ 通道， 现在已经知道该受体所在的位置。 鉴定和克隆 该受体的研究将提供一种更有效的筛选方式 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法。 受体的鉴定也将使我们能够探索其机制 此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+ 通道的筛选和最终基于受体的研究 合成生物模拟文库，因此将加快寻找 治疗盐潴留和高血压疾病的“理想药剂”。 本研究的成功完成，即合成了新的 正常尿钠排尿抗高血压药物及其鉴定 利尿钠受体对治疗具有重要意义 心血管疾病，也许提供了一种作用机制 维生素E复合物。