APPROACHES TO NATRIURETIC AND ANTIHYPERTENSIVE AGENTS

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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.