Inhibitory effects of hesperetin derivatives on guinea pig phosphodiesterases and Their ratios between high- and low-affinity rolipram binding

Hsin Te Hsu, Wen Hung Wang, Cheng Ying Han, Chun Nan Chen, Chi Ming Chen, Wun-Chang Ko

研究成果: 雜誌貢獻文章同行評審

6 引文 斯高帕斯(Scopus)

摘要

The phosphodiesterase (PDE)4 molecule exists as two distinct conformers, PDE4H and PDE4L, which have high and low affinities, respectively, for the selective PDE4 inhibitor, rolipram. The inhibition of PDE4H and PDE4L is associated with adverse responses, such as nausea, vomiting, and gastric hypersecretion, and with anti-inflammatory and bronchodilator effects, respectively. We determined the therapeutic (PDE4H/PDE4L) ratios of hesperetin-7-O-methylether, hesperetin-5,7,3′-O-trimethylether (HTME), hesperetin-7-O-acetate, hesperetin-7,3′-O-diacetate, hesperetin-5,7,3′-O-triacetate (HTA), hesperetin-5,7,3′-O-tripropionate, hesperetin-5,7,3′-O-tributyrate, hesperetin-5,7,3′-O-triisobutyrate, and hesperetin-5,7,3′-O-tripivatate, and compared these ratios to those of hesperetin, hesperetin-7,3′-O-dimethylether, hesperidin, and hesperidin-3′-O-methylether to identify derivatives with therapeutic ratios and to characterize the structure-activity relationships among these compounds. The activities of PDE isozymes 1 through 5 were measured using a two-step procedure using [3H]adenosine 3′,5′-cyclic monophosphate or [3H]guanosine 3′,5′-cyclic monophosphate as substrates. The inhibitory concentration (IC50) for 50% of PDE4 inhibition and effective concentration (EC50) for replacing 50% of [3H]rolipram binding on high-affinity rolipram-binding sites was taken as the PDE4L and PDE4H value, respectively. The HTME and the HTA dually inhibited PDE3 and PDE4, and displayed PDE4H/PDE4L ratios of 18.3 and 20.8, respectively, suggesting that they may be candidate drugs for treating asthma and chronic obstructive pulmonary disease (COPD) because the combined inhibition of PDE3 and PDE4 has synergistically anti-inflammatory and bronchodilator effects in COPD patients.
原文英語
頁(從 - 到)2120-2127
頁數8
期刊Journal of Pharmaceutical Sciences
102
發行號7
DOIs
出版狀態已發佈 - 七月 2013

ASJC Scopus subject areas

  • Pharmaceutical Science

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