Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol: role of pentylresorcinol moiety.

“Our recent work has shown that cannabidiol (CBD) exhibits the most potent direct inhibition of human cytochrome P450 1A1 (CYP1A1)…

These results suggest that the pentylresorcinol structure in CBD may have structurally important roles in direct CYP1A1 inhibition, although the whole structure of CBD is required for overall inhibition.”

http://www.ncbi.nlm.nih.gov/pubmed/23811569

“CYP1A1 regulates breast cancer proliferation and survival. This study supports the notion that CYP1A1 promotes breast cancer proliferation and survival… reduction of CYP1A1 levels is a potential strategy for breast cancer therapeutics.”  http://www.ncbi.nlm.nih.gov/pubmed/23576571

Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes.

“Inhibitory effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabidiol (CBD), and cannabinol (CBN), the three major constituents in marijuana, on catalytic activities of human cytochrome P450 (CYP) 1 enzymes were investigated.

These results indicated that CBD and CBN showed CYP1 isoform-selective direct inhibition and that CBD was characterized as a potent mechanism-based inhibitor of human CYP1 enzymes, especially CYP1A1.”

http://www.ncbi.nlm.nih.gov/pubmed/20117100

“CYP1A1 regulates breast cancer proliferation and survival. This study supports the notion that CYP1A1 promotes breast cancer proliferation and survival… reduction of CYP1A1 levels is a potential strategy for breast cancer therapeutics.”  http://www.ncbi.nlm.nih.gov/pubmed/23576571

The yin and yang of cannabis-induced psychosis: the actions of Δ(9)-tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia.

“There is substantial epidemiological evidence showing that cannabis increases the risk of psychosis, whereas other research suggests that schizophrenia patients self-medicate with the substance. These conflicting accounts may at least be partially explained by the two phytocannabinoids cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC) and their opposing actions on schizophrenia-related symptoms.

…propsychotic actions of THC… antipsychotic actions of CBD.

…animal studies… showing that CBD antagonises the neurobehavioural effects of THC, while others show the opposite, that CBD potentiates the actions of THC.

Various mechanisms are put forth to explain these divergent effects such as CBD antagonism at central CB1 receptors…”

…the present study suggests a beneficial property of a direct cannabinoid receptor agonist… and of CBD…”

http://www.ncbi.nlm.nih.gov/pubmed/22716133

http://www.thctotalhealthcare.com/category/schizophrenia/

A drug discovery case history of ‘delta-9-tetrahydrocannabinol, cannabidiol’.

“…the Cannabis sativa herb has been known for its therapeutic benefit for centuries… interest in the clinical potential of cannabinoid-based drugs escalated after the discovery of the endocannabinoid system… therapeutic applications of cannabinoids (plant-derived or synthetic)… may constitute a useful addition to the pharmacotherapeutic armamentarium in chronic conditions insufficiently alleviated by existing drugs.”  http://www.ncbi.nlm.nih.gov/pubmed/22646020

“The endocannabinoid system and its therapeutic exploitation.” http://www.ncbi.nlm.nih.gov/pubmed/15340387

“Cannabinoid receptors as therapeutic targets.” http://www.ncbi.nlm.nih.gov/pubmed/16402900

“Cannabinoids.” http://www.ncbi.nlm.nih.gov/pubmed/16266285

“Plant, synthetic, and endogenous cannabinoids in medicine.” http://www.ncbi.nlm.nih.gov/pubmed/16409166

Cannabidiol-2′,6′-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor.

“Cannabidiol (CBD), one of the major components of marijuana, is known to inhibit LOX activity…

15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.”

http://dmd.aspetjournals.org/content/37/8/1733.long

“15-lipoxygenase inhibitors as anti-atherosclerosis agents.”  http://www.ncbi.nlm.nih.gov/pubmed/18465533

Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1∆E9 mice.

“Patients suffering from Alzheimer’s disease (AD) exhibit a decline in cognitive abilities including an inability to recognise familiar faces…

The non-psychoactive phytocannabinoid cannabidiol (CBD) exerts neuroprotective, anti-oxidant and anti-inflammatory effects and promotes neurogenesis. CBD also reverses Aβ-induced spatial memory deficits in rodents.

This is the first study to investigate the effect of chronic CBD treatment on cognition in an AD transgenic mouse model.

Our findings suggest that CBD may have therapeutic potential for specific cognitive impairments associated with AD.”

http://www.ncbi.nlm.nih.gov/pubmed/24577515

Regulation of adenylate cyclase by cannabinoid drugs. Insights based on thermodynamic studies.

“The abilities of lipophilic cannabinoid drugs to regulate adenylate cyclase activity in neuroblastoma cell membranes were analyzed by thermodynamic studies…

These data suggest that, for the entropy-driven hormone-stimulated adenylate cyclase enzyme, less disorder of the system occurs in the presence of regulators that inhibit the enzyme via Gi.

In summary, thermodynamic data suggest that cannabidiol can influence adenylate cyclase by increasing membrane fluidity, but that the inhibition of adenylate cyclase by delta 9-tetrahydrocannabinol is not related to membrane fluidization.”

http://www.ncbi.nlm.nih.gov/pubmed/2554920

“Regulation of adenylate cyclase in a cultured neuronal cell line by marijuana constituents, metabolites of delta-9-tetrahydrocannabinol, and synthetic analogs having psychoactivity.” http://www.ncbi.nlm.nih.gov/pubmed/2830535

Recent advances in Cannabis sativa research: biosynthetic studies and its potential in biotechnology.

“Cannabinoids, consisting of alkylresorcinol and monoterpene groups, are the unique secondary metabolites that are found only in Cannabis sativa. Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabichromene (CBC) are well known cannabinoids and their pharmacological properties have been extensively studied. Recently, biosynthetic pathways of these cannabinoids have been successfully established. Several biosynthetic enzymes including geranylpyrophosphate:olivetolate geranyltransferase, tetrahydrocannabinolic acid (THCA) synthase, cannabidiolic acid (CBDA) synthase and cannabichromenic acid (CBCA) synthase have been purified from young rapidly expanding leaves of C. sativa. In addition, molecular cloning, characterization and localization of THCA synthase have been recently reported. THCA and cannabigerolic acid (CBGA), its substrate, were shown to be apoptosis-inducing agents that might play a role in plant defense. Transgenic tobacco hairy roots expressing THCA synthase can produce THCA upon feeding of CBGA. These results open the way for biotechnological production of cannabinoids in the future.”

http://www.ncbi.nlm.nih.gov/pubmed/17691992

Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation.

“Plant cannabinoids, like Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), activate/desensitize thermosensitive transient receptor potential (TRP) channels of vanilloid type-1 or -2 (TRPV1 or TRPV2). We investigated whether cannabinoids also activate/desensitize two other ‘thermo-TRP’s’, the TRP channels of vanilloid type-3 or -4 (TRPV3 or TRPV4), and if the TRPV-inactive cannabichromene (CBC) modifies the expression of TRPV1-4 channels in the gastrointestinal tract…

CONCLUSIONS:

Cannabinoids can affect both the activity and the expression of TRPV1-4 channels, with various potential therapeutic applications, including in the gastrointestinal tract.”

http://www.ncbi.nlm.nih.gov/pubmed/21726418

Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action.

“Two non-psychoactive cannabinoids, cannabidiol (CBD) and cannabichromene (CBC), are known to modulate in vitro the activity of proteins involved in nociceptive mechanisms, including transient receptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of ankyrin type-1 (TRPA1), the equilibrative nucleoside transporter and proteins facilitating endocannabinoid inactivation. Here we have tested these two cannabinoids on the activity of the descending pathway of antinociception…

CONCLUSIONS AND IMPLICATIONS:

CBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control.

These compounds might represent useful therapeutic agents with multiple mechanisms of action.”

http://www.ncbi.nlm.nih.gov/pubmed/20942863