Differential Inhibition of Multiple cAMP Phosphodiesterase Isozymes by Isoflavones and Tyrphostins

• Published in: Molecular pharmacology 2000-04, Vol.57 (4), p.738-745
• Main Authors: Nichols, M R, Morimoto, B H
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-GMP Phosphodiesterases - antagonists & inhibitors; Animals; Cattle; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 1; Cyclic Nucleotide Phosphodiesterases, Type 3; Enzyme Inhibitors - pharmacology; Humans; Isoenzymes - antagonists & inhibitors; Isoflavones - pharmacology; Phosphoric Diester Hydrolases; Structure-Activity Relationship; Tyrphostins - pharmacology
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.57.4.738

A series of isoflavone and tyrphostin compounds were found to inhibit the degradation of cAMP by several cyclic nucleotide phosphodiesterase (PDE) isozymes. Specific hydroxyl groups on the isoflavone structure were critical for PDE isozyme-selective inhibition. Replacement of the C-7 hydroxyl group of the isoflavone with a methoxy group raised the IC 50 for PDE1, PDE3, and PDE4. The absence of the C-5 hydroxyl group raised the IC 50 from 5 to >100 μM for PDE4, but actually lowered the IC 50 for PDE3 and PDE1. Replacement of the C-4′ hydroxyl group with a methoxy group raised the IC 50 for PDE3 and PDE1, yet only slightly changed the IC 50 for PDE4. Various tyrphostins were also potent inhibitors of PDE1, PDE3, and PDE4. The four-carbon side chained tyrphostins were much less potent; however, a very interesting pattern was observed in which removal of phenolic hydroxyls on the tyrphostin structure increased the potency for PDE1 and PDE3, but not PDE4. These results may help to explain some of the therapeutic and intracellular signaling effects of isoflavones and tyrphostins. Moreover, the isozyme selectivity demonstrated by the isoflavones and tyrphostins can serve as a pharmacophore for the design of specific PDE inhibitors.