Abstract
This paper describes the design, syntheses, and biological evaluations of novel ATP-sensitive potassium channel (K(ATP)) openers, benzopyranyl indoline and indole derivatives. Among those, two enantiomers of indoline-2-carboxylic ethyl esters (14, 18) showed the best cardioprotective activities both in vitro and in vivo, while their vasorelaxation potencies were very low (concentration for 50% inhibition of vasorelaxation >30 microM). The cardioprotective effect of 14 was completely reversed by 5-hydroxydecanoate, a selective mitochondrial K(ATP) blocker, indicating its provable protective mechanism through the mitochondrial K(ATP) opening. In addition, we performed conformational analyses using 2D-NMR, X-ray crystallography and molecular modeling to study the structure-activity relationships in this series of compounds.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism*
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Animals
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Benzopyrans / antagonists & inhibitors
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Benzopyrans / chemical synthesis
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Benzopyrans / chemistry
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Benzopyrans / pharmacology
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Cardiotonic Agents / antagonists & inhibitors
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Cardiotonic Agents / chemical synthesis
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Cardiotonic Agents / chemistry*
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Cardiotonic Agents / pharmacology*
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Crystallography, X-Ray
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Decanoic Acids / pharmacology
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Hydroxy Acids / pharmacology
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Indoles / antagonists & inhibitors
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Indoles / chemical synthesis
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Indoles / chemistry*
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Indoles / pharmacology*
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Conformation
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Myocardial Ischemia / prevention & control*
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Potassium Channels / drug effects*
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Potassium Channels / metabolism
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Rats
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Rats, Sprague-Dawley
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Stereoisomerism
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Structure-Activity Relationship
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Vasodilation / drug effects
Substances
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Benzopyrans
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Cardiotonic Agents
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Decanoic Acids
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Hydroxy Acids
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Indoles
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Potassium Channels
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5-hydroxydecanoic acid
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indoline
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Adenosine Triphosphate