Comparison of vasodilatory properties of 14,15-EET analogs: structural requirements for dilation.
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 Delta8 double bond had full activity and potency. However, the analogs with only a Delta5 or Delta11 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 Delta8 double bond, and a 14(S),15(R)-(cis)-epoxy group.
Falck
J R
JR
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
Krishna
U Murali
UM
Reddy
Y Krishna
YK
Kumar
P Srinagesh
PS
Reddy
K Malla
KM
Hittner
Sarah B
SB
Deeter
Christine
C
Sharma
Kamalesh K
KK
Gauthier
Kathryn M
KM
Campbell
William B
WB
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001158:Arteries; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology*; D066298:In Vitro Techniques; D013329:Structure-Activity Relationship; D014664:Vasodilation; D014665:Vasodilator Agents / Q000737:chemistry* / Q000494:pharmacology*
D014665:Vasodilator Agents; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid