17(R),18(S)-Epoxyeicosatetraenoic Acid, a Potent Eicosapentaenoic Acid (EPA) Derived Regulator of Cardiomyocyte Contraction: Structure–Activity Relationships and Stable Analogues

Abstract

17(R),18(S)-Epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca2+-overload with an EC50 ~1–2 nM. Structure-activity studies revealed a cis-Δ11,12- or Δ14,15-olefin and a 17(R),18(S)-epoxide are minimal structural elements for anti-arrhythmic activity whereas antagonist activity was often associated with the combination of a Δ14,15-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogs are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates.

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

“…Increasing evidence obtained in mammalian systems suggests the existence of GPCRs (G protein-coupled receptors) that specifically interact with selected sets of epoxy and hydroxy metabolites derived from n−6 and n−3 PUFAs [52,66,67]. Supporting the hypothesis that 17,18-EEQ may interact with similar targets in mammals and C. elegans, we found that a metabolically robust synthetic analogue, developed to mimic the effect of 17,18-EEQ on cardiomyocyte contractility [20], was also effective in modulating the locomotive activity of C. elegans. Further genetic analysis of the components mediating the 17,18-EEQ effects in C. elegans may facilitate the search for the thus far unknown receptors of CYPeicosanoids.…”

“…In mammals, CYP-eicosanoids act in an autocrine or paracrine manner and serve as second messengers of diverse hormones regulating the contractility of vascular smooth muscle cells and cardiomyoctes [20,60,61]. In C. elegans, 17,18-EEQ mediates the O2-ON response by increasing the activity of body muscle cells.…”

“…The compound used as 17,18-EEQ agonist was synthesized as described previously [20]. To prevent autooxidation, all stock solutions were prepared in an oxygen evacuated nitrogen chamber.…”

Role of CYP eicosanoids in the regulation of pharyngeal pumping and food uptake in Caenorhabditis elegans

“…Both quantity and purity of prepared eicosanoid stock solutions were confi rmed by LC/MS/MS measurements (data not shown). The compound used as 17,18-EEQ agonist was synthesized as described previously ( 21 ). To prevent autoxidation, all stock solutions, except for neurohormones, were prepared in an oxygen evacuated nitrogen chamber.…”

Microwave-Assisted Efficient Synthesis of Dialkylated Ureas from Ureas

“…[10] We have reported iridium-catalyzed synthesis of dialkylated ureas from ureas and alcohols. [11][12] The dialkylated ureas are important classess of biologically active compounds.However, the reaction required long reaction time (12 h). [13] Therefore, herein we wish to demonstrate that microwave irradiation significantly accelerated the process of the reaction.…”