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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 284; no. 1; pp. H337 - H349
• Main Authors: Falck, J. R, Krishna, U. Murali, Reddy, Y. Krishna, Kumar, P. Srinagesh, Reddy, K. Malla, Hittner, Sarah B, Deeter, Christine, Sharma, Kamalesh K, Gauthier, Kathryn M, Campbell, William B
• Format: Journal Article
• Language: English
• Published: United States 01.01.2003
• Subjects: 8,11,14-Eicosatrienoic Acid - analogs & derivatives; 8,11,14-Eicosatrienoic Acid - chemistry; 8,11,14-Eicosatrienoic Acid - pharmacology; Animals; Arteries; Cattle; Coronary Vessels - drug effects; Coronary Vessels - physiology; In Vitro Techniques; Structure-Activity Relationship; Vasodilation; Vasodilator Agents - chemistry; Vasodilator Agents - pharmacology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00831.2001

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