Abstract
During the search for naturally occurring cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitors, it was found that the extracts from Sophora flavescens exhibit potent inhibitory activity against cGMP PDE5 prepared from rat diaphragm. Therefore, the inhibitory activities of five flavonoids, kushenol H (1), kushenol K (2), kurarinol (3), sophoflavescenol (4) and kuraridine (5), isolated from S. flavescens were measured against cGMP PDE5 to identify potent cGMP PDE5 inhibitory constituents. Among tested compounds, sophoflavescenol (4), a C-8 prenylated flavonol, showed the most potent inhibitory activity (IC(50)=0.013 microM) against cGMP PDE5 with 31.5- and 196.2-fold selectivity over PDE3 and PDE4, respectively. Kinetic analysis revealed that sophoflavescenol was a mixed inhibitor of PDE5 with a K(i) value of 0.005 microM.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
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3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
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Animals
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Cyclic Nucleotide Phosphodiesterases, Type 3
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / isolation & purification
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Enzyme Inhibitors / pharmacology
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Flavonoids / chemistry
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Flavonoids / isolation & purification
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Flavonoids / pharmacology*
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Inhibitory Concentration 50
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Kinetics
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Rats
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Sophora / chemistry
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Flavonoids
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sophoflavescenol
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 3
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Cyclic Nucleotide Phosphodiesterases, Type 4
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3',5'-Cyclic-GMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Pde5a protein, rat