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

2 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and 1 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390 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 (ED 50 = 10 6 M). 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 8 double bond had full activity and potency. However, the analogs with only a 5 or 11 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 8 double bond, and a 14( S ),15( R )-( cis )-epoxy group. endothelium-derived hyperpolarizing factor; cytochrome P -450; arachidonic acid; epoxyeicosatrienoic acid