Chiral HPLC determination and stereoselective pharmacokinetics of tetrahydroberberine enantiomers in rats

Tetrahydroberberine (THB), a racemic mixture of (+)‐ and (?)‐enantiomer, is a biologically active ingredient isolated from a traditional Chinese herb Rhizoma corydalis (yanhusuo). A chiral high performance liquid chromatography method has been developed for the determination of THB enantiomers in rat plasma. The enantioseparation was carried out on a Chiral®‐AD column using methanol:ethanol (80:20, v/v) as the mobile phase at the flow rate 0.4 ml/min. The ultraviolet detection was set at 230 nm. The calibration curves were linear over the range of 0.01–2.5 μg/ml for (+)‐THB and 0.01‐5.0 μg/ml for (?)‐THB, respectively. The lower limit of quantification was 0.01 μg/ml for both (+)‐THB and (?)‐THB. The stereoselective pharmacokinetics of THB enantiomers in rats was studied after oral and intravenous administration at a dose of 50 and 10 mg/kg racemic THB (rac‐THB). The mean plasma levels of (?)‐THB were higher at almost all time points than those of (+)‐THB. (?)‐THB also exhibited greater C_max, and AUC_0–∞, smaller CL and V_d, than its antipode. The (?)/(+)‐enantiomer ratio of AUC_0–∞ after oral and intravenous administration were 2.17 and 1.43, respectively. These results indicated substantial stereoselectivity in the pharmacokinetics of THB enantiomers in rats. Chirality, 2012. © 2012 Wiley Periodicals, Inc.     

Biotransformation of tetrahydroberberine to berberine by enzymes prepared from cultured coptis japonica cells

Crude enzymes were extracted from cultured Coptis japonica cells producing large amounts of berberine. One of the enantiomers of tetrahydroberberine, (S)-(?)-tetrahydroberberine, was dehydrogenated to berberine by the enzyme system.     

Design,synthesis, and structure-activity relationships of novel 4,7,12,12a-tetrahydro-5H-thieno[3′,2′:3,4]pyrido[1,2-b]isoquinoline and 5,8,12,12a-tetrahydro-6H-thieno[2′,3′:4,5]pyrido[2,1-a]isoquinoline derivatives as cellular activators of adenosine 5′-monophosphate-activated protein kinase (AMPK)

To discover more derivatives with better glucose-lowering efficacy compared with berberine, twenty-three novel compounds with 4,7,12,12a-tetrahydro-5H-thieno[3′,2′:3,4]pyrido[1,2-b]isoquinoline or 5,8,12,12a-tetrahydro-6H-thieno[2′,3′:4,5]pyrido[2,1-a]isoquinoline cores were designed, synthesized, and biologically evaluated in vitro in continuation of our previous work on indirect activators of adenosine 5′-monophosphate-activated protein kinase (AMPK). Nine compounds effectively stimulated glucose consumption (>2.3-fold at 10 μM) in L6 myotube cells, and two compounds (4d and 4s) exhibited superior inhibitory activity (<57.6% at 5 μM) compared with berberine on gluconeogenesis in rat primary hepatocytes. Additionally, these compounds significantly up-regulated the phosphorylation of AMPK and its substrate, acetyl-CoA carboxylase (ACC) and slightly decreased the mitochondrial membrane potential in L6 myotube cells.