N-Heterocyclic carbene copper catalyzed quinoline synthesis from 2-aminobenzyl alcohols and ketones using DMSO as an oxidant at room temperature.

A facile and practical process for the synthesis of quinolines through an N-heterocyclic carbene copper catalyzed indirect Friedländer reaction from 2-aminobenzyl alcohol and aryl ketones using DMSO as an oxidant at room temperature is reported. A series of quinolines were synthesized in acceptable yields.

Peimine inhibits hERG potassium channels through the channel inactivation states.

BACKGROUND AND OBJECTIVE: Fritillaria is a Chinese traditional herb. It has a long history and many medicinal usages including antitussive, anti-inflammatory and pain relieving actions. It is also used as food. However, its cardiac safety has not been tested. Peimine is one of the main active compounds of Fritillaria. To be listed as an herb in the Chinese Pharmacopoeia, a special minimal percentage of Peimine in the dry sample of Fritillaria is required. The main concern for cardiac safety determination is the possible inhibition of hERG ion channels. Thus, Peimine was chosen to investigate its inhibitory effects on hERG channels. METHODS: Whole cell patch clamp technique was used. RESULTS AND CONCLUSION: We found that Peimine inhibited the hERG peak tail currents in a concentration dependent manner with an IC50 value of 43.7µM (n=4) by whole cell patch clamp techniques. Multiple results suggest that the inhibition was related to the channel inactivation. First, Peimine inhibition was significantly increased when the prepulse voltage was increased from -30mV to +10mV. Second, increasing prepulse length also significantly increased blockade by Peimine. Third, our finding that the inhibition by Peimine was use-dependent is related to changes in the inactivated state of the channel. Finally, the result that Peimine significantly decreased inactivation constant also suggested that Peimine affect the channel inactivation state. Mutation of Y652 to Alanine reduced sensitivity to Peimine, suggesting that Y652 is an important hERG binding sites for Peimine.

Interaction among hERG channel blockers is a potential mechanism of death in caffeine overdose.

Caffeine overdose death is due to cardiac arrest, but its mechanism has not been explored in detail. In this study, our data showed that caffeine significantly prolonged the heart rate-corrected QT interval (QTc) of rabbits in vivo (P<0.05; n=7). Caffeine was also found to be a hERG channel blocker with an IC50 of 5.04mM (n=5). Although these two findings likely link caffeine overdose death with hERG channel blockade, the amount of caffeine consumption needed to reach the IC50 is very high. Further study demonstrated that addition another hERG blocker could lower the consumption of caffeine significantly, no matter whether two hERG blockers share the same binding sites. Our data does not rule out other possibility, however, it suggests that there is a potential causal relationship between caffeine overdose death with hERG channel and the interaction among these hERG blockers.

Peimine, a main active ingredient of Fritillaria, exhibits anti-inflammatory and pain suppression properties at the cellular level.

Fritillaria is one of the most important herbs in Chinese traditional medicine and represents an annual ï¿¥700 million industry. It is often used as an anti-inflammatory, pain relieving and antitussive medicine. However, the mechanisms of these effects are still unclear. Peimine is one of active ingredients of Fritillaria. Using the patch-clamp technique, we profiled the action of Peimine against selected ion channels stably expressed in HEK 293 cell lines. Our data indicated that Peimine was not only able to block the Nav1.7 ion channel but also preferably inhibited the Kv1.3 ion channel. Thus, the study suggested potential mechanisms of Fritillaria as a pain relieving and anti-inflammatory herb.

Barium chloride impaired Kir2.1 inward rectification in its stably transfected HEK 293 cell lines.

Kir2.1 channel is a typical inward rectified channel with little outward currents when the membrane depolarized. Barium blocks the inward Kir2.1 currents in a voltage-dependent manner. However, in this study we found that barium would impair the rectification and open Kir2.1 outward currents at a depolarized voltage, causing increment of outward current amplitudes by 43±7% (n=5, P<0.01) after 200s barium application. In the meanwhile, a higher barium concentration did block the outward currents by 17.5±4.3% (n=4, P<0.01) and temporarily twisted current upward tendency. The increment was likely barium specific since both calcium and Kir2.1 specific blocker, Chloroethylclonidine (CEC), did not enhance the current amplitudes. The rectification of Kir2.1 was not recovered by washing barium off, which suggested a non-competitive mechanism. Since the currents occurred at phase 1, 2 of cardiac action potential, it would likely shorten the action potential plateau and it would decrease QT duration in electrocardiography (ECG).