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 Ca(2+)-overload with EC(50) ≈ 1-2 nM. Structure-activity studies revealed that a cis-Δ(11,12)- or Δ(14,15)-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 Δ(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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkenes / chemical synthesis*
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Alkenes / pharmacology
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Animals
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Animals, Newborn
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Anti-Arrhythmia Agents / chemical synthesis*
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Anti-Arrhythmia Agents / pharmacology
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Arachidonic Acids / chemical synthesis*
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Arachidonic Acids / pharmacology
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Binding Sites
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Calcium / metabolism
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Cells, Cultured
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Eicosapentaenoic Acid / analogs & derivatives*
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Eicosapentaenoic Acid / chemical synthesis*
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Eicosapentaenoic Acid / pharmacology
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Myocardial Contraction / drug effects*
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Myocytes, Cardiac / drug effects*
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Myocytes, Cardiac / physiology
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Rats
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Rats, Wistar
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Receptors, Eicosanoid / agonists
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Receptors, Eicosanoid / antagonists & inhibitors
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Alkenes
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Anti-Arrhythmia Agents
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Arachidonic Acids
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Receptors, Eicosanoid
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17,18-epoxy-5,8,11,14-eicosatetraenoic acid
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Eicosapentaenoic Acid
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Calcium