Structural requirements for activation of the 5-Oxo-6E, 8Z, 11Z, 14Z-eicosatetraenoic acid (5-Oxo-ETE) receptor: Identification of a mead acid metabolite with potent agonist activity

The 5-lipoxygenase product 5-oxo-6E, 8Z, 11Z, 14Z-eicosatetraenoic acid ( 5-oxo-ETE) is a potent chemoattractant for neutrophils and eosinophils, and its actions are mediated by the oxoeicosanoid ( OXE) receptor, a member of the G proteincoupled receptor family. To define the requirements for activation of the OXE receptor, we have synthesized a series of 5-oxo-6E, 8Z- dienoic acids with chain lengths between 12 and 20 carbons, as well as a series of 20-carbon 5-oxo fatty acids, either fully saturated or containing between one and five double bonds. The effects of these compounds on neutrophils ( calcium mobilization, CD11b expression, and cell migration) and eosinophils ( actin polymerization) were compared with those of 5-oxo-ETE. The C-12 and C-14 analogs were without appreciable activity, whereas the C-16 5-oxo- dienoic acid was a weak partial agonist. In contrast, the corresponding C 18 analog (5-oxo- 18: 2) was nearly as potent as 5-oxo-ETE. Among the C 20 analogs, the fully saturated compound had virtually no activity, whereas 5-oxo-6E-eicosenoic acid had only weak agonist activity. In contrast, 5-oxo-6E, 8Z, 11Z- eicosatrienoic acid (5-oxo-20: 3) and its 8-trans isomer were approximately equipotent with 5-oxo-ETE in activating granulocytes. Because of the potent effects of 5-oxo20: 3, we investigated its formation from Mead acid (5Z,8Z, 11Z-eicosatrienoic acid), which accumulates in dietary essential fatty acid deficiency, by neutrophils. The main Mead acid metabolite identified was 5-hydroxy- 6,8,11- eicosatrienoic acid, followed by 5-oxo-20: 3 and two 6-trans isomers of leukotriene B-3. We conclude that optimal activation of the OXE receptor is achieved with 5-oxo- ETE, 5- oxo- 18: 2, and 5- oxo- 20: 3, and that the latter compound could potentially be formed under conditions of essential fatty acid deficiency.