Comparison of vasodilatory properties of 14,15-EET analogs: structural requirements for dilation

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Abstract
Epoxyeicosatrienoic acids (EETs) are endothelium-derived eicosanoids that activate potassium channels, hyperpolarize the membrane, and cause relaxation. We tested 19 analogs of 14,15-EET on vascular tone to determine the structural features required for activity. 14,15-EET relaxed bovine coronary arterial rings in a concentration-related manner (ED50= 10−6M). Changing the carboxyl to an alcohol eliminated dilator activity, whereas 14,15-EET-methyl ester and 14,15-EET-methylsulfonimide retained full activity. Shortening the distance between the carboxyl and epoxy groups reduced the agonist potency and activity. Removal of all three double bonds decreased potency. An analog with a Δ8 double bond had full activity and potency. However, the analogs with only a Δ5 or Δ11 double bond had reduced potency. Conversion of the epoxy oxygen to a sulfur or nitrogen resulted in loss of activity. 14( S),15( R)-EET was more potent than 14( R),15( S)-EET, and 14,15-( cis)-EET was more potent than 14,15-( trans)-EET. These studies indicate that the structural features of 14,15-EET required for relaxation of the bovine coronary artery include a carbon-1 acidic group, a Δ8 double bond, and a 14( S),15( R)-( cis)-epoxy group.