Abstract
23-Alkyl-substituted and 6,23-alkyl-disubstituted derivatives of chenodeoxycholic acid are identified as potent and selective agonists of TGR5, a G-protein coupled receptor for bile acids (BAs). In particular, we show that methylation at the C-23(S) position of natural BAs confers a marked selectivity for TGR5 over FXR, while the 6alpha-alkyl substitution increases the potency at both receptors. The present results allow for the first time a pharmacological differentiation of genomic versus nongenomic effects mediated by BA derivatives.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bile Acids and Salts / chemical synthesis*
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Bile Acids and Salts / chemistry
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Bile Acids and Salts / pharmacology
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CHO Cells
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Cricetinae
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Cricetulus
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Crystallography, X-Ray
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DNA-Binding Proteins / agonists
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Humans
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Ligands
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Methylation
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Models, Molecular
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Molecular Structure
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Receptors, Cytoplasmic and Nuclear / agonists
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Receptors, G-Protein-Coupled / agonists*
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Stereoisomerism
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Structure-Activity Relationship
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Transcription Factors / agonists
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Ursodeoxycholic Acid / analogs & derivatives*
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Ursodeoxycholic Acid / chemical synthesis
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Ursodeoxycholic Acid / chemistry
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Ursodeoxycholic Acid / pharmacology
Substances
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6-ethyl-23-methyl-3,7-dihydroxycholan-24-oic acid
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Bile Acids and Salts
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DNA-Binding Proteins
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GPBAR1 protein, human
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Ligands
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Receptors, Cytoplasmic and Nuclear
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Receptors, G-Protein-Coupled
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Transcription Factors
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farnesoid X-activated receptor
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Ursodeoxycholic Acid