Abstract
A number of known 1,4-dihydropyridine CCBs were identified as having comparable potency to the steroidal MR antagonist eplerenone. Chiral resolution of mebudipine revealed that MR and CCB activity reside in opposite enantiomers. Small molecule X-ray crystal structures showed that the C4 stereochemistry of optimized selective MR analogues, e.g. 5, is consistent with MR-active mebudipine. Molecular modeling supports a binding pose consistent with that previously proposed for DHP diesters.
MeSH terms
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Animals
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Calcium Channel Blockers / chemistry
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Calcium Channel Blockers / pharmacology
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Calcium Channels, L-Type / metabolism
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Cell Line
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Crystallography, X-Ray
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Dihydropyridines / chemistry*
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Dihydropyridines / pharmacology
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Eplerenone
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Genes, Reporter
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Humans
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Luciferases / genetics
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Mineralocorticoid Receptor Antagonists*
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Models, Molecular
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Protein Binding
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Rats
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Receptors, Mineralocorticoid / chemistry
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Receptors, Mineralocorticoid / genetics
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Spironolactone / analogs & derivatives
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Spironolactone / chemistry
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Spironolactone / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Calcium Channel Blockers
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Calcium Channels, L-Type
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Dihydropyridines
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Mineralocorticoid Receptor Antagonists
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Receptors, Mineralocorticoid
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Spironolactone
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Eplerenone
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Luciferases