Cytochrome (CYP) P450 is now recognized as one of the three primary branches of the biomedically important arachidonate cascade together with the more intensively studied cyclooxygenase and lipoxygenase pathways. The primary metabolites of the cascade are subject to further enzymatic and non-enzymatic transformations resulting in a rich spectrum of bioactive products. Over the past decade, the participants of this Program Project have cogently demonstrated the relevance of the CYP cascade to renal physiology. In particular, products from the epoxygenase and omega/omega-I pathways have been implicated in vasoreactivity, ion and water transport, hormonal signaling, and hypertension. To expedite current investigations into the biogenesis, regulation, storage, metabolism, and mechanism of action of physiologically significant renal eicosanoids, this project proposes to: (1) Devise and conduct unambiguous, stereocontrolled total syntheses of bioactive arachidonate metabolites that influence kidney function. (2) Elucidate the structure-activity relationships (SAR) in bioactive renal eicosanoids. (3) Prepare synthetic eicosanoid analogs with modified chemical, metabolic, and/or pharmacological properties for use as selective agonists or antagonists as well as for the characterization, localization, and isolation of macromolecules that bind/recognize renal eicosanoids. (4) Design and evaluate selective metabolism inhibitors for use in vitro and/or in vivo.
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