Inhibitory effects of quercetin derivatives on phosphodiesterase isozymes and high-affinity [3H]-rolipram binding in guinea pig tissues

Agnes L F Chan, Hui Lin Huang, Hui Chi Chien, Chi Ming Chen, Chun Nan Lin, Wun Chang Ko

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Rolipram has high (PDE4H) and low (PDE4L) affinities for phosphodiesterase (PDE)-4, respectively. In general, it is believed that inhibitions by PDE4H and PDE4L are respectively associated with an adverse response and with anti-inflammatory and bronchodilating effects. This has provided a rational basis for designing new compounds with high PDE4H/PDE4L ratios. In the present study, we attempted to determine the PDE4H/PDE4L ratios of quercetin (1), qercetin-3-O-methylether (3-MQ, 2), quercetin-3,7,4′-O- trimethylether (ayanin, 3), quercetin-3,7,3′,4′-O- tetramethylether (QTME, 4), quercetin-3,5,7,3′,4′-O-petamethylether (QPME, 5), quercetin-3,5,7,3′,4′-O-pentaacetate (QPA, 6), and quercetin-3-O-methyl-5,7,3′,4′-O-tetraacetate (QMTA, 7). The activities of PDE1∼5, which were partially separated from homogenates of guinea pig lungs and hearts, were measured by a two-step procedure using adenosine 3′,5′-cyclic monophosphate (cAMP) with [ 3H]-cAMP or guanosine 3′,5′-cyclic monophosphate (cGMP) with [3H]-cGMP as substrates. The IC50 values of all of these compounds except quercetin (1), 3-MQ (2), and QMTA (7) on PDE1∼5 inhibition were determined. The anti-inflammatory effects of PDE4 inhibitors were reported to be associated with inhibition of PDE4 catalytic activity. Therefore, these IC50 values for PDE4 inhibition were taken as the PDE4L values. The effective concentration (EC50), at which one half of the [3H]-rolipram bound to high-affinity rolipram binding sites (HARBSs) of brain cell membranes was replaced, was defined as the PDE4H value. In the present results, the PDE4H/PDE4 L ratios of quercetin (1), ayanin (3), and QPME (5) were >30, >19, and 11, respectively (Table 1), which are higher than or equal to that of AWD12-281, the selective PDE4 inhibitor with the greatest potential currently undergoing clinical trials for treating asthma and chronic obstructive pulmonary disease.

Original languageEnglish
Pages (from-to)417-424
Number of pages8
JournalInvestigational New Drugs
Issue number5
Publication statusPublished - Oct 2008


  • 5′ cyclic monophosphate (cyclic AMP)
  • Adenosine 3′
  • Asthma
  • Chronic obstructive pulmonary disease (COPD)
  • High-affinity rolipram binding sites (HARBSs)
  • Phosphodiesterase isozymes 1∼5 (PDE1∼5)
  • Quercetin derivatives

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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