APPROACHES TO NATRIURETIC AND ANTIHYPERTENSIVE AGENTS

描述：我们计划的目标是机械性地理解 人体细胞外液容量的药物控制。冲向 为此，调查人员一直在分离、鉴定和合成 来自正常、尿毒症和充血性的内源性利钠因子 心力衰竭人类尿液。这个应用程序是一项利用 我们最近鉴定和合成了三个这样的因子LLU-α， LLU-Beta1和LLU-Gamma。其中最耐人寻味的LLU-Alpha是一种 生育酚的代谢物。利用这些线索，我们希望开发出 通过两种途径的“理想”利钠利钠降压药 方法，即：1)明智地应用生物模拟合成在 为了最大限度地实现理想，我们的药理特性 铅化合物和2)我们最有效的转化 优钾/利钠药(S)以高亲和力，放射性标记， 光亲和底物。这些化合物(S)将被用来 确定“利钠受体”。基于非常高的效力 ILU-α抑制Henle环TAL细胞的70pS K通道， 现在已经知道这种受体的位置。标识和克隆 将提供一种更有效的方式来筛选 合成化合物资料库(部分使用组合化学) 通过发展一种基于受体-配体相互作用的分析方法。 对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动态平衡的影响。 体内生物检测的这种双管齐下的方法与 针对70pS K通道的筛选和最终基于受体的研究 合成生物模拟文库，从而加快了对 是治疗盐滞留症和高血压病的理想药物。 这项研究的成功完成，即合成新的 利钠利钠降压药及其鉴定 利钠受体，将对治疗高血压病具有重要意义。 心血管疾病，也许提供了一种作用机制 维生素E复合体。

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.