rhyncophylline and corynoxeine

A new method based on liquid chromatography-tandem time-of-flight mass spectrometry was developed to identify the metabolites in rat urine after oral administration of YiGan San (YGS). Eighteen prototype compounds and four metabolites named 11-hydroxyhirsuteine, 19-carbonylhirsutine, 19-carbonyl-dihydrocorynantheine, and 18-hydroxy-geissoschizine methyl ether were identified. Subsequently, a method of high-performance liquid chromatography coupled with triple-quadrupole mass spectrometry was established for pharmacokinetic study of YGS in rat plasma. The concentration-time curves of four prototype compounds, senkyunolide I, ajmalicine, isocorynoxeine and rhynchophylline were constructed after an oral (9.1g YGS per kilogram of body weight) administration in rats. Method validation revealed excellent linearity over the range 220.00-0.55, 220.00-0.55, 21.40-0.05, and 19.80-0.05ng/mL for the four prototype compounds respectively. The stabilities results indicate that all of the analytes were stable in rat plasma in the autosampler for 24h, under freeze/thaw cycles (4 times in 24h), and at -20°C for one week. Residual analysis, heteroskedasticity test, and goodness-of-fit test were also performed to determine the accuracy of the linear regression method. The pharmacokinetic parameters were obtained. Four hours after administration, compound 11-hydroxyhirsuteine can be detected in rat plasma. Compared with purified ligustilide, YGS required a slightly longer period to reach maximum concentration (Cmax) in rat plasma.

Topics: Animals; Benzofurans; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Indole Alkaloids; Male; Oxindoles; Rats; Rats, Sprague-Dawley; Secologanin Tryptamine Alkaloids; Tandem Mass Spectrometry

Isorhynchophylline is a major oxindole alkaloid found in Uncaria species which have long been used in traditional Chinese medicine. Here, we investigated the effects of isorhynchophylline and isorhynchophylline-related alkaloids on 5-hydroxytryptamine (5-HT) receptor-mediated behavioural responses in mice and 5-HT-evoked current responses in Xenopus oocytes expressing 5-HT2A or 5-HT2C receptors. Isorhynchophylline dose-dependently inhibited 5-HT2A receptor-mediated head-twitch but not 5-HT1A receptor-mediated head-weaving responses evoked by 5-methoxy-N,N-dimethyltryptamine. Pretreatment with reserpine, a monoamine-depleting agent, enhanced the head-twitching, but did not influence the effect of isorhynchophylline on the behavioural response. Isocorynoxeine, an isorhynchophylline-related alkaloid in which the configuration of the oxindole moiety is the same as in isorhynchophylline, also reduced the head-twitch response in reserpinized mice over the same dose range as isorhynchophylline, while both rhynchophylline and corynoxeine, stereoisomers of isorhynchophylline and isocorynoxeine, did not. None of the alkaloids tested had an effect on meta-chlorophenylpiperazine-induced hypolocomotion, a 5-HT2C receptor-mediated behavioural response. In experiments in vitro, isorhynchophylline and isocorynoxeine dose-dependently and competitively inhibited 5-HT-evoked currents in Xenopus oocytes expressing 5-HT2A receptors, but had less of a suppressive effect on those in oocytes expressing 5-HT2C receptors. These results indicate that isorhynchophylline and isocorynoxeine preferentially suppress 5-HT2A receptor function in the brain probably via a competitive antagonism at 5-HT2A receptor sites and that the configuration of the oxindole moiety of isorhynchophylline is essential for their antagonistic activity at the 5-HT2A receptor.

Topics: Alkaloids; Aminopyridines; Animals; Behavior, Animal; Brain; Dose-Response Relationship, Drug; Female; Indole Alkaloids; Ketanserin; Male; Membrane Potentials; Methoxydimethyltryptamines; Mianserin; Mice; Mice, Inbred ICR; Motor Activity; Oocytes; Oxindoles; Patch-Clamp Techniques; Piperazines; Rats; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Xenopus

We have previously reported on the Ca2+-blocking activity and active constituents of natural products. In the course of screening, Uncariae ramulus et uncus, a chinese herbal medicine, was found to possess such activity. In this paper, we attempted to characterize its active constituent which plays an important role in Ca2+-blocking activity. Its active principles were identified to be oxyindole-type alkaloids, rhynchophylline, corynoxeine, isorhynchophylline and isocorynoxeine, that showed inhibitory effects, similar to that of verapamil, on contractile response to high concentration of potassium ion (rats), CaCl2 (rats), norepinephrine in normal and Ca2+-free medium (rats and rabbits) and 45Ca2+-uptake (rats) in thoracic aorta with an activity two orders of magnitude less than the activity of verapamil.

Topics: Alkaloids; Animals; Calcium; Calcium Channel Blockers; Drugs, Chinese Herbal; Indole Alkaloids; Muscle Contraction; Oxindoles; Rabbits; Rats; Rats, Inbred Strains