Isocorynoxeine

Planta Med. 2015 Jan;81(1):46-55.

Isolation and identification of twelve metabolites of isocorynoxeine in rat urine and their neuroprotective activities in HT22 cell assay.[Pubmed: 25519834]

Isocorynoxeine, one of the major alkaloids from Uncaria Hook, shows the effects of lowering blood pressure, vasodilatation, and protection against ischemia-induced neuronal damage.
METHODS AND RESULTS:
In this paper, the metabolism of Isocorynoxeine was investigated in rats. Twelve metabolites and the parent drug were isolated by using solvent extraction and repeated chromatographic methods, and determined by spectroscopic methods including UV, MS, NMR, and CD experiments. Seven new compounds were identified as 11-hydroxyIsocorynoxeine, 5-oxoisocorynoxeinic acid-22-O-β-D-glucuronide, 10-hydroxyIsocorynoxeine, 17-O-demethyl-16,17-dihydro-5-oxoIsocorynoxeine, 5-oxoisocorynoxeinic acid, 21-hydroxy-5-oxoIsocorynoxeine, and oxireno[18, 19]-5-oxoIsocorynoxeine, together with six known compounds identified as Isocorynoxeine, 18,19-dehydrocorynoxinic acid, 18,19-dehydrocorynoxinic acid B, corynoxeine, Isocorynoxeine-N-oxide, and corynoxeine-N-oxide. Possible metabolic pathways of Isocorynoxeine are proposed. Furthermore, the activity assay for the parent drug and some of its metabolites showed that Isocorynoxeine exhibited a significant neuroprotective effect against glutamate-induced HT22 cell death at the maximum concentration. However, little or weak neuroprotective activities were observed for M-3, M-6, M-7, and M-10.
CONCLUSIONS:
Our present study is important to further understand their metabolic fate and disposition in humans.

Eur J Pharmacol. 2005 Jul 11;517(3):191-9.

Suppressive effects of isorhynchophylline on 5-HT2A receptor function in the brain: behavioural and electrophysiological studies.[Pubmed: 15963493]

Isorhynchophylline is a major oxindole alkaloid found in Uncaria species which have long been used in traditional Chinese medicine.
METHODS AND RESULTS:
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.
CONCLUSIONS:
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.

J Asian Nat Prod Res. 2015;17(4):384-90.

Metabolites of isocorynoxeine in rats after its oral administration.[Pubmed: 25633191]

This work presents the metabolites of Isocorynoxeine (ICOR), which is one of four bioactive tetracyclic oxindole alkaloids isolated from Uncaria hooks used commonly in the traditional Chinese medicines and Kampo medicines.
METHODS AND RESULTS:
After oral administration of 40 mg kg(-1) ICOR to rats, bile was drained and analyzed by LC-MS. Two phase I metabolites, namely 11-hydroxyIsocorynoxeine (M1) and 10-hydroxyIsocorynoxeine (M2), and two phase II metabolites, namely 11-hydroxyIsocorynoxeine 11-O-β-D-glucuronide (M3) and 10-hydroxyIsocorynoxeine 10-O-β-D-glucuronide (M4), were isolated from rat excreta and bile, respectively, whose structures were elucidated on the basis of CD, NMR, and MS.

J Nat Prod. 2008 Jul;71(7):1271-4.

Alkaloids from the leaves of Uncaria rhynchophylla and their inhibitory activity on NO production in lipopolysaccharide-activated microglia.[Pubmed: 18588343]

Two new isomeric alkaloids, 18,19-dehydrocorynoxinic acid B (1) and 18,19-dehydrocorynoxinic acid (2), were isolated from the CHCl3 extract of the leaves of Uncaria rhynchophylla, together with four known rhynchophylline-type alkaloids, corynoxeine (3), Isocorynoxeine (4), rhynchophylline (5), and isorhynchophylline (6), and an indole alkaloid glucoside, vincoside lactam (7).
METHODS AND RESULTS:
The structures of compounds 1 and 2 were elucidated by spectroscopic methods including UV, IR, HREIMS, 1D and 2D NMR, and CD experiments. The activity assay showed that compounds 3-6, with a C-16 carboxylic ester group, and 7 exhibited inhibitory activity on lipopolysaccharide (LPS)-induced NO release in primary cultured rat cortical microglia (IC 50: 13.7-19.0 microM). However, only weak inhibitory activity was observed for compounds 1 and 2, with a C-16 carboxylic acid group (IC 50: >100 microM).