14,15-EET analogs: characterization of structural requirements for agonist and antagonist activity in bovine coronary arteries.
Arachidonic acid metabolites contribute to the regulation of vascular tone and therefore tissue blood flow. The vascular endothelium metabolizes arachidonic acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs. The placement of the epoxide group can occur on any of the double bonds of arachidonic acid resulting in four EET regioisomers; 5,6-, 8,9-, 11,12- and 14,15-EET. In the vasculature, EETs are key components of cellular signaling cascades that culminate in the activation of smooth muscle potassium channels to induce membrane hyperpolarization and vascular relaxation. In some vasculatures such as bovine coronary arteries, EET regioisomers are equipotent in inducing relaxations, while in other arteries, a specific EET regioisomer induces relaxation while others do not. Therefore, the position of the double bonds and/or the epoxide group may alter vascular agonist activity. This observation suggests that small alterations in the chemical structure of EETs can significantly impact vascular activity. To explore this hypothesis, we synthesized a series of EET analogs and characterized their vasodilator agonist and antagonist activity in bovine coronary arteries. In this chapter, we first review the mechanisms of EET-dependent relaxations in bovine coronary arteries to familiarize the reader with the role of EETs in these arteries. The second component is a synopsis of the functional characterization of the 14,15-EET analogs and the resulting description of structural components required for vascular dilator activity. Lastly, we discussed the characterization of three 14,15-EET analogs with specific EET-antagonist activity and compared this to the activity of similar 11,12-EET analogs. These studies have revealed that specific structural components of the 14,15-EET molecule are critical for dilator activity and that alteration of these components influences agonist activity and may confer antagonist properties.
Gauthier
Kathryn M
KM
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Falck
J R
JR
Reddy
L Manmohan
LM
Campbell
William B
WB
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid