Minor Cannabinoids as Inhibitors of Skin Inflammation: Chemical Synthesis and Biological Evaluation.

Despite millennia of therapeutic plant use, deliberate exploitation of Cannabis's diverse biomedical potential has only recently gained attention. Bioactivity studies focus mainly on cannabidiol (CBD) and tetrahydrocannabinol (THC) with limited information about the broader cannabinome's "minor phytocannabinoids". In this context, our research targeted the synthesis of minor cannabinoids containing a lateral chain with 3 or 4 carbon atoms, focusing on cannabigerol (CBG) and cannabichromene (CBC) analogues. Using known and innovative strategies, we achieved the synthesis of 11 C3 and C4 analogues, five of which were inhibitors of skin inflammation, with the CBG-C4 ester derivative emerging as the most potent compound.

Easy and Accessible Synthesis of Cannabinoids from CBD.

Cannabidiol (CBD), a prominent phytocannabinoid found in various Cannabis chemotypes, is under extensive investigation for its therapeutic potential. Moreover, because it is nonpsychoactive, it can also be utilized as a functional ingredient in foods and supplements in certain countries, depending on its legal status. From a chemical reactivity point of view, CBD can undergo conversion into different structurally related compounds both during storage and after the consumption of CBD-based products. The analytical determination of these compounds is of paramount concern due to potential toxicity and the risk of losing the active ingredient (CBD) title. Consequently, the complete stereoselective total synthesis of representative CBD-derived compounds has become a matter of great interest. The synthesis of pure CBD-derived compounds, achievable in a few synthetic steps, is essential for preparing analytical standards and facilitating biological studies. This paper details the transformation of the readily available CBD into Δ8-THC, Δ9-THC, Δ8-iso-THC, CBE, HCDN, CBDQ, Δ6-iso-CBD, and 1,8-cineol cannabinoid (CCB). The described protocols were executed without the extensive use of protecting groups, avoiding tedious purifications, and ensuring complete control over the structural features.

Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB2 Receptor Derived from the Natural Product Cannabidiol.

Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site, and a negative allosteric modulator, when it binds to the allosteric site of the cannabinoid CB2 receptor. Molecular dynamic simulations and site-directed mutagenesis studies have identified the allosteric site near the receptor entrance. This knowledge has permitted to perform structure-guided design of negative and positive allosteric modulators of the CB2 receptor with potential therapeutic utility.

Origin of Δ9-Tetrahydrocannabinol Impurity in Synthetic Cannabidiol.

Introduction: Cannabidiol (CBD), the nonintoxicating constituent of cannabis, is largely employed for pharmaceutical and cosmetic purposes. CBD can be extracted from the plant or chemically synthesized. Impurities of psychotropic cannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and Δ8-THC have been found in extracted CBD, thus hypothesizing a possible contamination from the plant. Materials and Methods: In this study, synthetic and extracted CBD samples were analyzed by ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry and the parameters that can be responsible of the conversion of CBD into THC were evaluated by an accelerated stability test. Results: In synthetic and extracted CBD no trace of THC species was detected. In contrast, CBD samples stored in the dark at room temperature on the benchtop for 3 months showed the presence of such impurities. Experiments carried out under inert atmosphere in the absence of humidity or carbon dioxide led to no trace of THC over time even at high temperature. Conclusions: The results suggested that the copresence of carbon dioxide and water from the air could be the key for creating the acidic environment responsible for the cyclization of CBD. These findings suggest that it might be appropriate to review the storage conditions indicated on the label of commercially available CBD.

Pharmacokinetic investigation of synthetic cannabidiol oral formulations in healthy volunteers.

Recent advances in the research of medicinal cannabis has placed the non-intoxicating cannabinoid cannabidiol (CBD) at the front of scientific research. The reasons behind this popularity is the compound's therapeutic properties, alongside a safe profile of administration lacking addictive properties such as euphoric state of mind and a wide dosing range. Oral administration of CBD is challenging due to poor solubility in the gastro-intestinal system and susceptibility to extensive first pass metabolism. As a result, the practice in clinic and investigational trials is to administer cannabinoids in edible oils or oil-based solutions. Nonetheless, reported pharmacokinetics of cannabinoids and CBD in particular are not uniform among research groups and are affected by the vehicle of administration. The purpose of the work presented here is to investigate oral absorption processes of synthetic CBD when given in different oral formulations in healthy volunteers. The study design was a three way, blind, cross-over single administration study of 12 healthy male volunteers. CBD was administered in powder form, dissolved in sesame oil and in self-nano-emulsifying drug delivery system (SNEDDS). Administration of CBD in lipid-based vehicles resulted in a significant increase in Cmax and AUC of CBD, as compared to powder form. Overall plasma exposure of CBD did not differ between sesame oil vehicle and the SNEDDS formulation. However, administration of CBD in pure oil resulted in two absorption behaviors of early and delayed absorption among subjects, as opposed to SNEDDS platform that resulted in a uniform early absorption profile. Results of this trial demonstrate the importance of solubilization process of lipophilic drugs such as CBD and demonstrated the ability of the nano formulation to achieve a reliable, predictable PK profile of the drug. These findings offer a standardized oral formulation for the delivery of cannabinoids and contribute data for the growing field of cannabinoid pharmacokinetics.

Synthetic Access to Cannabidiol and Analogs as Active Pharmaceutical Ingredients.

Cannabinoids have surely been one of the most widely self-administered drugs other than caffeine. The U.S. FDA recently approved one cannabinoid-based drug whose active pharmaceutical ingredient (API) is cannabidiol (CBD). The long history of individual use of cannabis for a wide range of conditions has sparked great interest in other uses of CBD, in ethical drugs and botanical supplements as well as in foods and nonprescription wellness products. CBD may be sourced from cannabis plants but can also be prepared synthetically, the topic of this review.

A Novel Alternative in the Treatment of Detrusor Overactivity? In Vivo Activity of O-1602, the Newly Synthesized Agonist of GPR55 and GPR18 Cannabinoid Receptors.

The aim of the research was to assess the impact of O-1602-novel GPR55 and GPR18 agonist-in the rat model of detrusor overactivity (DO). Additionally, its effect on the level of specific biomarkers was examined. To stimulate DO, 0.75% retinyl acetate (RA) was administered to female rats' bladders. O-1602, at a single dose of 0.25 mg/kg, was injected intra-arterially during conscious cystometry. Furthermore, heart rate, blood pressure, and urine production were monitored for 24 h, and the impact of O-1602 on the levels of specific biomarkers was evaluated. An exposure of the urothelium to RA changed cystometric parameters and enhanced the biomarker levels. O-1602 did not affect any of the examined cystometric parameters or levels of biomarkers in control rats. However, the O-1602 injection into animals with RA-induced DO ameliorated the symptoms of DO and caused a reversal in the described changes in the concentration of CGRP, OCT3, BDNF, and NGF to the levels observed in the control, while the values of ERK1/2 and VAChT were significantly lowered compared with the RA-induced DO group, but were still statistically higher than in the control. O-1602 can improve DO, and may serve as a promising novel substance for the pharmacotherapy of bladder diseases.

Is cannabidiol a scheduled controlled substance? Origin makes the difference.

Cannabidiol (CBD) is the main cannabinoid naturally occurring in hemp. It has recently attracted the attention of the scientific community because of its numerous pharmacological activities. However, its legal status changes depending on whether it is chemically synthesized or extracted from the plant: extracted CBD is a scheduled controlled substance, whereas synthetic CBD is not under control. In Europe, extracted CBD is excluded from the cosmetic ingredients of the CosIng database. Given the confusion surrounding these different forms of CBD, there is an urgent need for clarity to shed light from both a regulatory and a chemical point of view. The impurity profiles of synthetic and natural CBD are different and could currently represent the only means to distinguish the origin of this substance.

Monocyclic Quinone Structure-Activity Patterns: Synthesis of Catalytic Inhibitors of Topoisomerase II with Potent Antiproliferative Activity.

The monocyclic 1,4-benzoquinone, HU-331, the direct oxidation product of cannabidiol, inhibits the catalytic activity of topoisomerase II but without inducing DNA strand breaks or generating free radicals, and unlike many fused-ring quinones exhibits minimal cardiotoxicity. Thus, monocyclic quinones have potential as anticancer agents, and investigation of the structural origins of their biological activity is warranted. New syntheses of cannabidiol and (±)-HU-331 are here reported. Integrated synthetic protocols afforded a wide range of polysubstituted resorcinol derivatives; many of the corresponding novel 2-hydroxy-1,4-benzoquinone derivatives are potent inhibitors of the catalytic activity of topoisomerase II, some more so than HU-331, whose monoterpene unit replaced by a 3-cycloalkyl unit conferred increased antiproliferative properties in cell lines with IC50 values extending below 1 mM, and greater stability in solution than HU-331. The principal pharmacophore of quinones related to HU-331 was identified. Selected monocyclic quinones show potential for the development of new anticancer agents.

Synthetic Strategies for (-)-Cannabidiol and Its Structural Analogs.

(-)-Cannabidiol ((-)-CBD), a non-psychoactive phytocannabinoid from Cannabis, and its structural analogs have received growing attention in recent years because of their potential therapeutic benefits, including neuroprotective, anti-epileptic, anti-inflammatory, anxiolytic, and anti-cancer properties. (-)-CBD and its analogs have been obtained mainly based on extraction from the natural source; however, the conventional extraction-based methods have some drawbacks, such as poor quality control along with purification difficulty. Chemical-synthetic strategies for (-)-CBD could tackle these issues, and, additionally, generate novel (-)-CBD analogs that exhibit advanced biological activities. This review concisely summarizes the historic and recent milestones in the synthetic strategies for (-)-CBD and its analogs.

VCE-004.3, a cannabidiol aminoquinone derivative, prevents bleomycin-induced skin fibrosis and inflammation through PPARγ- and CB2 receptor-dependent pathways.

BACKGROUND AND PURPOSE: The endocannabinoid system and PPARγ are important targets for the development of novel compounds against fibrotic diseases such as systemic sclerosis (SSc), also called scleroderma. The aim of this study was to characterize VCE-004.3, a novel cannabidiol derivative, and study its anti-inflammatory and anti-fibrotic activities. EXPERIMENTAL APPROACH: The binding of VCE-004.3 to CB1 and CB2 receptors and PPARγ and its effect on their functional activities were studied in vitro and in silico. Anti-fibrotic effects of VCE-004.3 were investigated in NIH-3T3 fibroblasts and human dermal fibroblasts. To assess its anti-inflammatory and anti-fibrotic efficacy in vivo, we used two complementary models of bleomycin-induced fibrosis. Its effect on ERK1/2 phosphorylation induced by IgG from SSc patients and PDGF was also investigated. KEY RESULTS: VCE-004.3 bound to and activated PPARγ and CB2 receptors and antagonized CB1 receptors. VCE-004.3 bound to an alternative site at the PPARγ ligand binding pocket. VCE-004.3 inhibited collagen gene transcription and synthesis and prevented TGFß-induced fibroblast migration and differentiation to myofibroblasts. It prevented skin fibrosis, myofibroblast differentiation and ERK1/2 phosphorylation in bleomycin-induced skin fibrosis. Furthermore, it reduced mast cell degranulation, macrophage activation, T-lymphocyte infiltration, and the expression of inflammatory and profibrotic factors. Topical application of VCE-004.3 also alleviated skin fibrosis. Finally, VCE-004.3 inhibited PDGF-BB- and SSc IgG-induced ERK1/2 activation in fibroblasts. CONCLUSIONS AND IMPLICATIONS: VCE-004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPARγ/CB2 agonist and CB1 receptor modulator that could be considered for the development of novel therapies against different forms of scleroderma.

New Methods for the Synthesis of Cannabidiol Derivatives.

Cannabidiol (CBD) is one of the most abundant components isolated from Cannabis sativa. However, CBD is a nonpsychotropic phytocannabinoid. In the last decade, there has been a growing interest in its therapeutic effects. This is why this natural product represents a lead structure for the development of new cannabinoid compounds. Even though chemistry of CBD has been explored for more than 30 years, the synthesis of only a few derivatives has been described. This chapter first reviews the synthetic methods for the preparation of CBD and derivatives. Then, it describes procedures for the synthesis of N-heterocyclic derivatives of CBD with, in particular, the preparation and structural characterization of 5-alkyl-2-(1H-pyrazol-3-yl)benzene-1,3-diol.

Neuropsychiatric and General Interactions of Natural and Synthetic Cannabinoids with Drugs of Abuse and Medicines.

BACKGROUND & OBJECTIVE: Cannabis is the most widely used illicit drug. The two most important natural cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The THC content of cannabis has been increasing during the last years and recently appeared in the market as a series of synthetic cannabinoids with potent agonist activity. Recreational users frequently combine cannabis with other drugs of abuse as alcohol, amphetamines and derivatives, nicotine and cocaine. In addition, these subjects can be taking medicines for acute and chronic medical conditions. The increasing use of medicinal cannabis for chronic pain and neurological and psychiatric disorders can produce potential interactions with medications used for the symptomatic treatment of these or other diseases. CONCLUSION: THC and CBD are metabolized mainly in the liver by cytochrome P-450 isoenzymes (mainly CYP2Cs and CYP3A4). In vitro studies indicate that THC and CBD both inhibit CYP1A1, 1A2 and 1B1 enzymes, and recent studies have indicated that CBD is also a potent inhibitor of CYP2C19 and CYP3A4. Both cannabinoids may interact with other medications metabolized by the same pathway or by inducers/inhibitors of the isoenzymes. Cannabis produces sedation, impairs psychomotor performance, and increases blood pressure and heart rate. Pharmacodynamic interactions with other sedatives can potentiate the central effects but can be decreased by psychostimulants. This review focuses on the interactions between cannabinoids and alcohol, other drugs of abuse, and prescription medicines.

Enantioselective total syntheses of (+)-hostmanin A, (-)-linderol A, (+)-methyllinderatin and structural reassignment of adunctin E.

A one-step protocol has been developed for the enantioselective synthesis of hexahydrodibenzofuran derivatives using a modified Friedel-Crafts reaction. The developed method was applied to the synthesis of a series of natural products including (+)-hostmanin A, (+)-methyllinderatin, and (-)-linderol A. The synthetic and spectroscopic data investigations led to the structural reassignment of natural product adunctin E, which was further confirmed by single-crystal X-ray analysis.

High-pressure Diels-Alder cycloadditions between benzylideneacetones and 1,3-butadienes: application to the synthesis of (R,R)-(-)- and (S,S)-(+)-Delta8-tetrahydrocannabinol.

High-pressure Diels-Alder reactions of various alkoxy/alkyl-substituted benzylideneacetones with methyl-1,3-butadienes are reported. Activation by high pressure (8-11 kbar) in combination with the mild Lewis acid HfCl(4).2THF allows these reactions to efficiently and regioselectively produce a series of ortho-substituted cyclohexenyl-benzene cycloadducts, that are useful precursors for the expeditious construction of the privileged 6,6-dimethyltetrahydro-6H-benzo[c]chromene skeleton. Application to the synthesis of Delta(8)-trans-THC in both enantiomeric pure forms is based on the successful resolution of selected cycloadduct by the SAMP-hydrazone method.

High pressure Diels-Alder approach to hydroxy-substituted 6a-cyano-tetrahydro-6H-benzo[c]chromen-6-ones: a route to delta(6)-cis-cannabidiol.

Diels-Alder cycloaddition reactions of 3-cyanocoumarin, hydroxy-substituted 3-cyanocoumarins and mesyl-substituted 3-cyano-coumarins with methyl-1,3-butadienes carried out under high pressure (11 kbar) are reported. Activation by high pressure allows these reactions to proceed satisfactorily under mild conditions to produce 6a-cyano-hydroxy- and 6a-cyano-mesyl-tetrahydro-6H-benzo[c]chromen-6-ones in moderate to excellent yield. The synthesis of cis-1-hydroxy-9-methyl-3-pentyl-6a,7,10,10a-tetrahydro-benzo[c]chromen-6-one as precursor of Delta(6)-3,4-cis-cannabidiol (Delta(6)-cis-CBD) and Delta(8)-cis-tetrahydrocannabinol (Delta(8)-cis-THC) is outlined.

Cannabidiol--recent advances.

The aim of this review is to present some of the recent publications on cannabidiol (CBD; 2), a major non-psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms. The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity.

Synthesis of cannabidiols via alkenylation of cyclohexenyl monoacetate.

[reaction: see text] Because of the lack of potency binding to the receptors responsible for psychoactivity, cannabidiol has received much attention as a lead compound to develop a nonpsychotropic drug. Herein, we establish a method to access not only cannabidiol but also its analogues. The key reaction is nickel-catalyzed allylation of 2-cyclohexene-1,4-diol monoacetate with a new reagent, (alkenyl)ZnCl/TMEDA, which gives a S(N)2-type product with 94% regioselectivity in good yield.

New cannabidiol derivatives: synthesis, binding to cannabinoid receptor, and evaluation of their antiinflammatory activity.

Cannabidiol (CBD) and cannabidiol dimethyl hephtyl (CBD-DMH) were hydrogenated to give four different epimers. The new derivatives were evaluated for their ability to modulate the production of reactive oxygen intermediates (ROI), nitric oxide (NO), and tumor necrosis factor (TNF-alpha) by murine macrophages, and for their binding to the cannabinoid receptor (CB(1)). Surprisingly, we found that these derivatives exhibit good binding to CB(1). In addition hydrogenated CBD and CBD-DMH demonstrate bioactivities different from their original compounds.

Enantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptors.

(-)-Cannabidiol (CBD) is a major, non psychotropic constituent of cannabis. It has been shown to cause numerous physiological effects of therapeutic importance. We have reported that CBD derivatives in both enantiomeric series are of pharmaceutical interest. Here we describe the syntheses of the major CBD metabolites, (-)-7-hydroxy-CBD and (-)-CBD-7-oic acid and their dimethylheptyl (DMH) homologs, as well as of the corresponding compounds in the enantiomeric (+)-CBD series. The starting materials were the respective CBD enantiomers and their DMH homologs. The binding of these compounds to the CB(1) and CB(2) cannabinoid receptors are compared. Surprisingly, contrary to the compounds in the (-) series, which do not bind to the receptors, most of the derivatives in the (+) series bind to the CB(1) receptor in the low nanomole range. Some of these compounds also bind weakly to the CB(2) receptor.