“Breaking bud”: the effect of direct chemical modifications of phytocannabinoids on their bioavailability, physiological effects, and therapeutic potential

Banerjee, Abhinandran Ronnie; Hayward, John; Trant, John F.

doi:10.1039/d3ob00068k

Cited by 5 publications

(5 citation statements)

References 85 publications

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“…Although CBG and CBN are protected by the 2018 AIA interpretation, their low relative abundance within the cannabis plant indicates that products containing these compounds are likely sourced from non-compliant precursors or synthetic cannabinoids . One of the hallmarks indicative of cannabinoid synthesis, particularly from the acid-catalyzed isomerization of CBD, − , is exo-THC (i.e., Δ 9,11 -THC), a psychoactive cannabinoid exhibiting a similar potency to Δ 8 -THC. It is reasonable to assume that DMS can be used to separate the argentinated forms of CBG, CBN, and exo-THC in tandem with Δ 9 -THC, Δ 8 -THC, CBD, and CBN, but before doing so, it is necessary to discern the fragmentation patterns of the argentinated precursors such that MRM can be employed.…”

Section: Resultsmentioning

confidence: 99%

Argentination: A Silver Bullet for Cannabinoid Separation by Differential Mobility Spectrometry

2023

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As the legality of cannabis continues to evolve globally, there is a growing demand for methods that can accurately quantitate cannabinoids found in commercial products. However, the isobaric nature of many cannabinoids, along with variations in extraction methods and product formulations, makes cannabinoid quantitation by mass spectrometry (MS) challenging. Here, we demonstrate that differential mobility spectrometry (DMS) and tandem-MS can distinguish a set of seven cannabinoids, five of which are isobaric: Δ 9 -tetrahydrocannabinol (Δ 9 -THC), Δ 8 -THC, exo-THC, cannabidiol, cannabichromene, cannabinol, and cannabigerol. Analytes were detected as argentinated species ([M + Ag] + ), which, when subjected to collision-induced dissociation, led to the unexpected discovery that argentination promotes distinct fragmentation patterns for each cannabinoid. The unique fragment ions formed were rationalized by discerning fragmentation mechanisms that follow each cannabinoid's MS 3 behavior. The differing fragmentation behaviors between species suggest that argentination can distinguish cannabinoids by tandem-MS, although not quantitatively as some cannabinoids produce small amounts of a fragment ion that is isobaric with the major fragment generated by another cannabinoid. By adding DMS to the tandem-MS workflow, it becomes possible to resolve each cannabinoid in a pure N 2 environment by deconvoluting the contribution of each cannabinoid to a specific fragmentation channel. To this end, we used DMS in conjunction with a multiple reaction monitoring workflow to assess cannabinoid levels in two cannabis extracts. Our methodology exhibited excellent accuracy, limits of detection (10−20 ppb depending on the cannabinoid), and linearity during quantitation by standard addition (R 2 > 0.99).

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Section: Resultsmentioning

confidence: 99%

Argentination: A Silver Bullet for Cannabinoid Separation by Differential Mobility Spectrometry

2023

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“…50,51 Moreover, CBD (1) has fast metabolism and also generates metabolites by modifying the sites adjacent to double bonds. 52,53 Considering this in mind, we generated a reduced form of CBD (1), viz., THCBD (4) and DHCBD (5) (details provided in Schemes 1 and 2), that might slow down the metabolism. The reduced cannabidiol (THCBD, 4) has been synthesized previously and studied for inflammatory potential.…”

Section: ■ Discussionmentioning

confidence: 99%

“…coli ATCC-25922, respectively (Table and Figure S1 of the Supporting Information). Among the isolated phytocannabinoids, CBD has shown potent activity with an MIC of 4 μg/mL, comparable with the literature-reported value. , CBD ( 1 ) has already been approved by US FDA against drug-resistant refractory epilepsy. , CBD ( 1 ) also has another potential against several other diseases and is being investigated in several clinical trials. − Despite its approval as a drug, CBD ( 1 ) lacks drug-likeness and has poor oral bioavailability, limiting its full utilization. , Moreover, CBD ( 1 ) has fast metabolism and also generates metabolites by modifying the sites adjacent to double bonds. , Considering this in mind, we generated a reduced form of CBD ( 1 ), viz., THCBD ( 4 ) and DHCBD ( 5 ) (details provided in Schemes and ), that might slow down the metabolism. The reduced cannabidiol (THCBD, 4 ) has been synthesized previously and studied for inflammatory potential. , The synthesized reduced cannabidiol (THCBD, 4 , and DHCBD, 5 ) has also been tested against S.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Antibacterial Potential of Semisynthetic Phytocannabinoid: Tetrahydrocannabidiol (THCBD) as a Potential Antibacterial Agent against Sensitive and Resistant Strains of Staphylococcus aureus

Cham,

Deepika,

Bhat

et al. 2023

ACS Infect. Dis.

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Antimicrobial resistance (AMR) is one of the most challenging problems and is responsible for millions of deaths every year. We therefore urgently require new chemical entities with novel mechanisms of action. Phytocannabinoids have been adequately reported for the antimicrobial effect but not seriously pursued because of either stringent regulatory issues or poor drug-like properties. In this regard, the current work demonstrated the antibacterial potential of tetrahydrocannabidiol (THCBD, 4), a semisynthetic phytocannabinoid, against Staphylococcus aureus, the second-most widespread bug recognized by the WHO. THCBD (4) was generated from cannabidiol and subjected to extensive antibacterial screening. In in vitro studies, THCBD (4) demonstrated a potent MIC of 0.25 μg/mL against Gram-positive bacteria, S. aureus ATCC-29213. It is interesting to note that THCBD (4) has demonstrated strong effectiveness against efflux pump-overexpressing (SA-1199B, SA-K2191, SA-K2192, and Mup r -1) and multidrug-resistant (MRSA-15187) S. aureus strains. THCBD (4) has also shown a good effect in kill kinetic assays against ATCC-29213 and MRSA-15187. In the checkerboard assay, THCBD (4) has shown additive/indifference effects with several well-known clinically used antibiotics, tetracycline, mupirocin, penicillin G, and ciprofloxacin. THCBD (4) also exhibited good permeability in the artificial skin model. Most importantly, THCBD (4) has significantly reduced CFU in mice's in vivo skin infection models and also demonstrated decent plasma exposure with 16− 17% oral bioavailability. Acute dermal toxicity of THCBD (4) suggests no marked treatment-related impact on gross pathophysiology. This attractive in vitro and in vivo profile of plant-based compounds opens a new direction for new-generation antibiotics and warrants further detailed investigation.

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“…4 Since the initial discovery of THC and other related cannabinoids, 5,6 numerous modifications and analogs have been synthesized to define the structure-activity relationship (SAR) of THC with both CB1 and CB2. 7 THC analogues differ primarily at two major sites: the ring system and the alkyl chain (Figure 1A). According to Bow Figure 1 Overview of THC and its ring system, highlighting the various side chain lengths discussed in the article.…”

Section: Introductionmentioning

confidence: 99%

A mechanistic model explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1

Shahbazi,

Meister,

Mohammadzadeh

et al. 2024

Preprint

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CB1, a member of the G protein-coupled receptor class, is the putative protein target of THC, the psychoactive component of cannabis. To better identify new synthetic cannabinoids with increased activity, all cannabinoids with reported experimental binding to the CB1 receptor were modelled in silico to build a predictive model for CB1 affinity of small molecules. Computationally derived affinity is not sufficient in and of itself to predict binding, but coupled with the experimental evidence that ligands enter the receptor from the membrane rather than solvent, we provide a model that accurately describes the binding of these molecules by incorporating a correction factor for relative hydrophobicity. In addition, we propose a mechanism of action for partial CB1 agonists based on molecular dynamics simulations of THC homologues, modelling long time scale structural changes in the CB1 receptor. Together, the affinity model, and the mechanism of agonism/antagonism can allow for the computational prediction of both the effective behaviour and potency of novel cannabinoids, and several such predictions are made.

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“Breaking bud”: the effect of direct chemical modifications of phytocannabinoids on their bioavailability, physiological effects, and therapeutic potential

Abstract: Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two "major cannabinoids". However, their incorporation into clinical and nutraceutical preparations is challenging, owing to their limited bioavailability, low water solubility, and variable...

Cited by 5 publications

References 85 publications

Argentination: A Silver Bullet for Cannabinoid Separation by Differential Mobility Spectrometry

Argentination: A Silver Bullet for Cannabinoid Separation by Differential Mobility Spectrometry

Exploring the Antibacterial Potential of Semisynthetic Phytocannabinoid: Tetrahydrocannabidiol (THCBD) as a Potential Antibacterial Agent against Sensitive and Resistant Strains of Staphylococcus aureus

A mechanistic model explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1

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