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

摘要

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-Δ^11,12- or Δ^14,15-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 Δ^14,15-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.