Glaucine

Biochem Pharmacol. 2013 Nov 15;86(10):1497-506.

Studies on the in vivo contribution of human cytochrome P450s to the hepatic metabolism of glaucine, a new drug of abuse.[Pubmed: 23988488]

Glaucine ((S)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-methyl-4H-dibenzo [de,g]quinoline), main isoquinoline alkaloid of Glaucium flavum (Papaveraceae), is used as antitussive, but also as recreational drug of abuse. Glaucine was mainly metabolized by O- and N-demethylation to four isomers in rats. So far, only scarce pharmacokinetic data were available. Therefore, the aim of the presented study was to assess the involvement of the ten most important cytochrome P450 (P450) isoforms in the main metabolic steps and determination of their kinetic parameters using the metabolite formation approach.
METHODS AND RESULTS:
Reference standards of investigated metabolites were synthesized for quantification. In addition, the impact of isomeric standards was tested for calibration and the use of simple peak area ratios on the kinetic constants and resulting contribution of P450 isoforms on estimated hepatic clearance. Kinetic profiles of all metabolite formations followed classic Michaelis-Menten behavior. Km values were between 25 and 140μM, Vmax between 0.10 and 1.92pmol/min/pmol. Using the relative activity factor approach, the hepatic clearance was calculated to be 27 and 73% for 2-O-demethylation by CYP1A2 and CYP3A4, 82, 3, and 15% for 9-O-demethylation by CYP1A2, CYP2C19, and CYP2D6, and finally <1 and 99% for N-demethylation by CYP2D6 and CYP3A4.
CONCLUSIONS:
These data were confirmed by inhibition tests. The calibration mode for determination of the metabolite concentrations had no relevant impact on the estimation of in vivo hepatic clearance of Glaucine. As Glaucine was metabolized via three initial steps and different P450 isoforms were involved in the hepatic clearance of Glaucine, a clinically relevant interaction with single inhibitors should not be expected.

Bioorg Med Chem. 2008 Aug 1;16(15):7457-61.

Cinnamoyl- and hydroxycinnamoyl amides of glaucine and their antioxidative and antiviral activities.[Pubmed: 18590964 ]

The aporphine alkaloid Glaucine has been converted into 3-aminomethylGlaucine and its free amino group has been linked to cinnamic, ferulic, sinapic, o-, and p-coumaric acids.
METHODS AND RESULTS:
The antioxidative potential of the synthesized amides was studied against DPPH(*) test. All of the tested compounds demonstrated higher radical scavenging activity than Glaucine and 3-aminomethylGlaucine, and lower antioxidative effect than the free hydroxycinnamic acids. The newly synthesized compounds were tested in vitro for antiviral activity against viruses belonging to different taxonomic groups.

Immunopharmacol Immunotoxicol. 2015 Feb;37(1):56-62.

Acetylated derivative of glaucine inhibits joint inflammation in collagenase-induced arthritis.[Pubmed: 25328086]

Osteoarthritis (OA) has become by far the most common joint disorder. A number of studies using OA animal models have explored the effects of agents that can modulate bone metabolism. In the present study, we investigated the effect of acetylated derivative of plant alkaloid Glaucine (ADG) on experimental OA in mice.
METHODS AND RESULTS:
Arthritis was induced by two intraarticular (i.a.) injections of collaganase. Histopathological changes were observed through hematoxylin and eosine (H&E), safranin O and toluidine blue staining. Differentiation of bone marrow (BM) cells was evaluated by tartarate-resistant acid phosphatase (TRAP) assay. The expression of phospho-Janus kinase 2 (pJAK2) and phospho signal transducer and activator of transcription3 (pSTAT3) expression in the joints was determined by immunohistochemistry. We established that ADG significantly decreased cell infiltration (2.32 ± 0.14 versus 1.62 ± 0.13), cartilage loss (2.42 ± 0.12 versus 1.12 ± 0.10) and bone erosion (1.76 ± 0.13 versus 1.04 ± 0.14) in arthritic mice. It appeared that the substance inhibited in a dose-dependent manner osteoclast differentiation in vitro. ADG suppressed the expression of pJAK2 in the joint and partially affected the expression of pSTAT3.
CONCLUSIONS:
Present results suggest that ADG is a suitable candidate for further development as an anti-arthritic agent.

Mol Cell Biochem. 2015 May;403(1-2):85-94.

Glaucine inhibits breast cancer cell migration and invasion by inhibiting MMP-9 gene expression through the suppression of NF-κB activation.[Pubmed: 25670016]

Matrix metalloproteinase-9 (MMP-9) plays a central role in the invasion and metastasis of various types of cancer cells.
METHODS AND RESULTS:
Here, we demonstrate that Glaucine, an alkaloid isolated from the plant Corydalis turtschaninovii tuber (Papaveraceae), can inhibit the migration and invasion of human breast cancer cells. We further show that Glaucine significantly blocks phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 expression and activity in a dose-dependent manner. Results from reporter gene and electrophoretic mobility shift assays revealed that Glaucine inhibits MMP-9 expression by suppressing activation of the nuclear transcription factor nuclear factor-κB (NF-κB). Moreover, Glaucine attenuates PMA-induced IκBα degradation and nuclear translocation of NF-κB. Finally, we also found that Glaucine inhibits invasion and MMP-9 expression in the highly metastatic MDA-MB-231 breast cancer cell line.
CONCLUSIONS:
Taken together, our findings indicate that the MMP-9 inhibitory activity of Glaucine and its abilities to attenuate IκBα and NF-κB activities may be therapeutically useful as a novel means of controlling breast cancer growth and invasiveness.

Fitoterapia. 2009 Oct;80(7):411-4.

Toll-like receptor-mediated anti-inflammatory action of glaucine and oxoglaucine.[Pubmed: 19481591]

Two isochinoline alkaloids, Glaucine and oxoGlaucine were investigated for their suggested anti-inflammatory influence concerning nitric oxide and cytokine production.
METHODS AND RESULTS:
Mouse peritoneal macrophages were stimulated with different Toll-like receptor (TLR) ligands such as LPS for TLR4, zymosan for TLR2 and CpG for TLR9. The alkaloids inhibited TNF-alpha and IL-6 production induced by these ligands. In regard to IL-12 suppressive effect was registered in the case of CpG stimulation.
CONCLUSIONS:
Glaucine succeeded to enhance LPS and zymosan-induced IL-10 production. The reduction of pro-inflammatory cytokines and increase of anti-inflammatory IL-10 are indicative for their use in different acute and chronic inflammatory diseases.