cannabidiol and cannabidiol-dimethyl-ether

Considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of fiber-type cannabis plant, and it has been reported to possess diverse biological activities. Although CBD is obtained from non-enzymatic decarboxylation of its parent molecule, cannabidiolic acid (CBDA), several studies have investigated whether CBDA itself is biologically active. In the present report, the author summarizes findings indicating that; 1) CBDA is a selective cyclooxygenase-2 (COX-2) inhibitor, and ii) CBDA possesses an anti-migrative potential for highly invasive cancer cells, apparently through a mechanism involving inhibition of cAMP-dependent protein kinase A, coupled with an activation of the small GTPase, RhoA. Further, the author introduces recent findings on the medicinal chemistry and pharmacology of the CBD derivative, CBD-2',6'-dimethyl ether (CBDD), that exhibits inhibitory activity toward 15-lipoxygenase (15-LOX), an enzyme responsible for the production of oxidized low-density lipoprotein (LDL). These studies establish CBD as both an important experimental tool and as a lead compound for pharmaceutical development. In this review, the author further discusses the potential uses of CBD and its derivatives in future medicines.

Topics: Animals; Breast Neoplasms; Cannabidiol; Cannabinoids; Cannabis; Cell Movement; Cells, Cultured; Chemistry, Pharmaceutical; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 2 Inhibitors; Decarboxylation; Drug Discovery; Female; Humans; Lipoproteins, LDL; Lipoxygenase Inhibitors; Phytotherapy; rhoA GTP-Binding Protein

The biological activities of cannabidiol (CBD), a major non-psychotropic constituent of the fiber-type cannabis plant, have been examined in detail (e.g., CBD modulation of body weight in mice and rats). However, few studies have investigated the biological activities of cannabidiol-2',6'-dimethyl ether (CBDD), a dimethyl ether derivative of the parent CBD. We herein focused on the effects of CBDD on body weight changes in mice, and demonstrated that it stimulated body weight gain in apolipoprotein E (ApoE)-deficient BALB/c. KOR/Stm Slc-Apoe(shl) mice, especially between 10 and 20 weeks of age.

Topics: Age Factors; Animals; Apolipoproteins E; Cannabidiol; Male; Mice, Inbred BALB C; Mice, Transgenic; Stimulation, Chemical; Weight Gain

15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein (ox-LDL), a major causal factor for atherosclerosis. Both enzymatic (15-LOX) and non-enzymatic (Cu(2+)) mechanisms have been proposed for the production of ox-LDL. We have recently reported that cannabidiol-2',6'-dimethyl ether (CBDD) is a selective and potent inhibitor of 15-LOX-catalyzed linoleic acid oxygenation (Takeda et al., Drug Metab. Dispos., 37, 1733-1737 (2009)). In the LDL, linoleic acid is present as cholesteryl linoleate, the major fatty acid esterified to cholesterol, and is susceptible to oxidative modification by 15-LOX or Cu(2+). In this investigation, we examined the efficacy of CBDD on i) 15-LOX-catalyzed oxygenation of cholesteryl linoleate, and ii) ox-LDL formation catalyzed by 15-LOX versus Cu(2+)-mediated non-enzymatic generation of this important mediator. The results obtained demonstrate that CBDD is a potent and selective inhibitor of ox-LDL formation generated by the 15-LOX pathway. These studies establish CBDD as both an important experimental tool for characterizing 15-LOX-mediated ox-LDL formation, and as a potentially useful therapeutic agent for treatment of atherosclerosis.

Topics: Antioxidants; Arachidonate 15-Lipoxygenase; Atherosclerosis; Cannabidiol; Cholesterol Esters; Cholesterol, LDL; Copper; Humans; Lipoproteins, LDL; Oxidation-Reduction

The inhibitory effect of nordihydroguaiaretic acid (NDGA) (a nonselective lipoxygenase (LOX) inhibitor)-mediated 15-LOX inhibition has been reported to be affected by modification of its catechol ring, such as methylation of the hydroxyl group. Cannabidiol (CBD), one of the major components of marijuana, is known to inhibit LOX activity. Based on the phenomenon observed in NDGA, we investigated whether or not methylation of CBD affects its inhibitory potential against 15-LOX, because CBD contains a resorcinol ring, which is an isomer of catechol. Although CBD inhibited 15-LOX activity with an IC(50) value (50% inhibition concentration) of 2.56 microM, its monomethylated and dimethylated derivatives, CBD-2'-monomethyl ether and CBD-2',6'-dimethyl ether (CBDD), inhibited 15-LOX activity more strongly than CBD. The number of methyl groups in the resorcinol moiety of CBD (as a prototype) appears to be a key determinant for potency and selectivity in inhibition of 15-LOX. The IC(50) value of 15-LOX inhibition by CBDD is 0.28 microM, and the inhibition selectivity for 15-LOX (i.e., the 5-LOX/15-LOX ratio of IC(50) values) is more than 700. Among LOX isoforms, 15-LOX is known to be able to oxygenate cholesterol esters in the low-density lipoprotein (LDL) particle (i.e., the formation of oxidized LDL). Thus, 15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.

Topics: Animals; Cannabidiol; Dose-Response Relationship, Drug; Humans; Lipoxygenase Inhibitors; Masoprocol; Methylation; Molecular Structure; Structure-Activity Relationship

Oxidative metabolism of cannabidiol monomethyl ether (CBDM), one of the components of marihuana, was studied in the guinea pig. Cannabielsoin monomethyl ether (CBEM) was found to be formed with hepatic microsomes by gas chromatography-mass spectrometry (GC-MS). Experiments using various modifiers of enzymatic reaction suggested that, as in the case of cannabielsoin (CBE) formation from canabidiol (CBD), CBEM was formed from CBDM by the monooxygenase system including cytochrome P450. When cannabidiol dimethyl ether (CBDD), in which phenolic hydroxyl groups of CBD are masked with methyl groups, was incubated with liver microsomes and an reduced nicotinamide adenine dinucleotide phosphate-generating system, 1S,2R-epoxy-CBDD was identified by GC-MS. The epoxy metabolite was also found in the liver of a guinea pig pretreated with CBDD (100 mg/kg, intraperitoneally) 1 h before sacrifice. Rate of 1S,2R-epoxide metabolism was slower than that of 1R,2S-epoxy-CBDD under the conditions, as in the microsomal oxidation of CBDD described above. These results indicate that 1S,2R-epoxides are formed from CBD, CBDM and CBDD and that the epoxides are quickly converted to elsoin-type metabolites in the cases of CBD and CBDM.

Topics: Animals; Biotransformation; Cannabidiol; Guinea Pigs; In Vitro Techniques; Male