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

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 EC50 approximate to 1-2 nM. Structure-activity studies revealed that a cis-Delta(11,12)- or Delta(4,15)-olefin and a 17(R),18(S)-epoxide are minimal structural elements for antiarrhythmic activity whereas antagonist activity was often associated with the combination of a Delta(14,15)-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogues are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates.