Inhibition of the different cyclic nucleotide phosphodiesterase isoforms separated from rat brain by flavonoid compounds.
A series of synthetic pentasubstituted analogs of quercetin were evaluated for their ability to inhibit the various phosphodiesterase isoforms resolved from rat brain cytosol by isoelectric focusing. All the tested compounds were more potent in inhibiting the calcium plus calmodulin-independent isoforms than the dependent ones. Out of the two calcium-independent cyclic AMP-specific isoforms present in brain preparations, the Rolipram-sensitive enzyme proved to be the most sensitive to flavonoid inhibition. In contrast with the antidepressant compound Rolipram which is totally devoid of anticalmodulin property, these flavonoid derivatives exhibited anticalmodulin activity as illustrated by their higher inhibitory potency toward the calmodulin-dependent isoform in the presence of calcium plus calmodulin than in the presence of EGTA and by the ability of [3H] penta-O-ethylquercetin to bind to calmodulin in a calcium-dependent way.
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Laboratoire de chimie biologique, Institut National des Sciences Appliquées de Lyon, Unité INSERM, France.
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Pacheco
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002118:Calcium / Q000494:pharmacology; D002147:Calmodulin / Q000494:pharmacology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D003600:Cytosol / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D007700:Kinetics; D051381:Rats; D013329:Structure-Activity Relationship
D002147:Calmodulin; D005419:Flavonoids; D007527:Isoenzymes; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D002118:Calcium