| Summary: | 碩士 === 臺北醫學大學 === 藥理學研究所 === 94 === Selective phosphodiesterase (PDE)-4 inhibitors have anti-inflammatory and bronchodilating effects. Therefore, these drugs will be helpful in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Aim of this study was investigation for the relationships between the structures and inhibitory effects of hesperetin esters on phosphodiesterase 1~5 activities. In the furture, we hope can synthesize more useful drugs to ameliorate asthma and COPD. In our labolatory, we homogenized the lungs and hearts of guinea pigs, and then centrifuged. The supernatant was chromatographed over Q-sepharose, an anion exchange resin. The bound proteins (phosphodiesterases, PDEs) were eluted with various concentrations of NaCl, and separated into PDE1, PDE5, PDE2 and PDE4 in the order, whereas PDE3 was separated from hearts. Cyclic nucleotide phosphodiesterase activitices were measured by a two-step procedure according the method of Thompson and Appleman, using cAMP with [3H]-cAMP or cGMP with [3H]-cGMP as substrate.
We synthesized seven hesperetin esters, including hesperetin-7-O-acetate (1), hesperetin-7,3'-O-diacetate (2), hesperetin-5,7,3'-O-triacetate (3), hesperetin-5,7,3'-O-tripropionate (4), hesperetin-5,7,3'-O-tributyrate (5), hesperetin-5,7,3'-O-triisobutyrate (6), and hesperetin-5,7,3'-O-tripivatate (7). According to our results showed that compound 1 and 2 selectively inhibited PDE4 with an IC50 value around 30 μM and 60 μM (Table 2). Compound 3 exhibited dual inhibition of PDE3/PDE4 with an IC50 value of 18.2 and 14.4 M, respectively. It also inhibited PDE2 with a low potency (IC50, 39.3 M), but inhibited neither PDE1 nor PDE5. Compound 4 selectively inhibitied PDE3 (IC50, 28.0 M). However compound 5~7 had no effects on PDE1~5 activities. In conclusion, compound 3 has a potential to develop a drug for the treatment of asthma and COPD. Compound 4, whereas, has a potential to be a cardiac tonic.
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