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Cannabinoid-Related Compounds for Medical Use

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioactive Lipids".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 33675

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Dr. Cristoforo Silvestri

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Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Université Laval, Laval, QC, Canada
Interests: cannabinoids/endocannabinoids and related bioactive lipids; obesity; metabolism; adipogenesis; lipid and glucose metabolism
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Dr. Alessia Ligresti

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Istituto di Chimica Biomolecolare (ICB), Consiglio Nazionale delle Ricerche (CNR), Pozzuoli, Italy
Interests: role of bioactive lipids such as endocannabinoids and pro resolving lipid mediators in metabolic and oncological disease; development of cannabinoid-based therapeutic applications in oncological and neurological diseases; role of cell bioenergetics and metabolic phenotypes in disease progression

Dr. Fabio Arturo Iannotti

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Istituto di Chimica Biomolecolare (ICB), Consiglio Nazionale delle Ricerche (CNR), Pozzuoli, Italy
Interests: cannabinoids; TRP channels; PPAR receptors; rare skeletal muscle diseases
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Special Issue Information

Dear Colleagues,

The cannabinoid receptor CB1 was so named as it was identified as the pharmacological target directing the main psychoactive effects of the cannabis-derived phytocannabinoid delta 9-tetrahydrocannabinol (THC). However, while the THC–CB1 ligand–receptor interaction is the canonical cannabinoid signaling pathway, THC is a polypharmacological agent, which we now know is able to modulate the activity of various receptors, channels and enzymes. Additionally, the cannabis plant produces a plethora of THC-related phytocannabinoids, each with (poly)pharmacological proprieties. Therefore, cannabis is a source of many compounds, with some being more abundant than others, that have received great attention owing to their potential therapeutic proprieties, as evidenced by the historical use of cannabis to treat a variety of ailments including epilepsy, pain, cancer, inflammation etc.

To date, only the phytocannabinoids THC and cannabidiol (CBD) have obtained approval from regulatory bodies as therapeutic agents for a limited number of maladies; however, a flourishing body of research suggests that other cannabinoids have clinical potential for many diseases as well. Moreover, some phytocannabinoids are known to directly or indirectly target proteins including receptors and metabolic enzymes of the endocannabinoid system (ECS), whose fine-tuning activity is known to control numerous physiological and pathophysiological processes.

This Special Issue, titled “Cannabinoid-Related Compounds for Medical Use”, will highlight recent developments in medical research on the application of phytocannabinoids, endocannabinoids and their congeners as well as pharmacological agents mimicking their activity.

Dr. Cristoforo Silvestri
Dr. Alessia Ligresti
Dr. Fabio Arturo Iannotti
Guest Editors

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Keywords

cannabis
cannabinoid
phytocannabinoid
endocannabinoids
cannabinoid pharmacology
medical research

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Published Papers (9 papers)

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12 pages, 1117 KiB

Open AccessArticle

The Anti-Inflammatory Effects of Cannabis sativa Extracts on LPS-Induced Cytokines Release in Human Macrophages

by Mariia Zaiachuk, Santosh V. Suryavanshi, Nazar Pryimak, Igor Kovalchuk and Olga Kovalchuk

Molecules 2023, 28(13), 4991; https://doi.org/10.3390/molecules28134991 - 25 Jun 2023

Cited by 5 | Viewed by 6590

Abstract

Inflammation is the response of the innate immune system to any type of injury. Although acute inflammation is critical for survival, dysregulation of the innate immune response leads to chronic inflammation. Many synthetic anti-inflammatory drugs have side effects, and thus, natural anti-inflammatory compounds are still needed. Cannabis sativa L. may provide a good source of anti-inflammatory molecules. Here, we tested the anti-inflammatory properties of cannabis extracts and pure cannabinoids in lipopolysaccharide (LPS)-induced inflammation in human THP-1 macrophages. We found that pre-treatment with cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), or extracts containing high levels of CBD or THC reduced the level of induction of various cytokines. The CBD was more efficient than THC, and the extracts were more efficient than pure cannabinoids. Finally, IL-6, IL-10, and MCP-1 cytokines were most sensitive to pre-treatments with CBD and THC, while IL-1β, IL-8, and TNF-α were less responsive. Thus, our work demonstrates the potential of the use of cannabinoids or/and cannabis extracts for the reduction of inflammation and establishes IL-6 and MCP-1 as the sensitive markers for the analysis of the effect of cannabinoids on inflammation in macrophages. Full article

(This article belongs to the Special Issue Cannabinoid-Related Compounds for Medical Use)

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29 pages, 14955 KiB

Open AccessArticle

Systematic Modification of the Substitution Pattern of the 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Scaffold Enabled the Discovery of New Ligands with High Affinity and Selectivity for the Cannabinoid Type 2 Receptor

by Claudia Mugnaini, Magdalena Kostrzewa, Marta Casini, Poulami Kumar, Valeria Catallo, Marco Allarà, Laura Guastaferro, Antonella Brizzi, Marco Paolino, Andrea Tafi, Christelos Kapatais, Gianluca Giorgi, Federica Vacondio, Marco Mor, Federico Corelli and Alessia Ligresti

Molecules 2023, 28(13), 4958; https://doi.org/10.3390/molecules28134958 - 24 Jun 2023

Cited by 1 | Viewed by 1488

Abstract

Selective ligands of the CB2 receptor are receiving considerable attention due to their potential as therapeutic agents for a variety of diseases. Recently, 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide derivatives were shown to act at the CB2 receptor either as agonists or as inverse agonists/antagonists in vitro and to have anti-osteoarthritic activity in vivo. In this article, we report the synthesis, pharmacological profile, and molecular modeling of a series of twenty-three new 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamides with the aim of further developing this new class of selective CB2 ligands. In addition to these compounds, seven other analogs that had been previously synthesized were included in this study to better define the structure–activity relationship (SAR). Ten of the new compounds studied were found to be potent and selective ligands of the CB2 receptor, with K_i values ranging from 48.46 to 0.45 nM and CB1/CB2 selectivity indices (SI) ranging from >206 to >4739. In particular, compounds 54 and 55 were found to be high-affinity CB2 inverse agonists that were not active at all at the CB1 receptor, whereas 57 acted as an agonist. The functional activity profile of the compounds within this structural class depends mainly on the substitution pattern of the pyrazole ring. Full article

(This article belongs to the Special Issue Cannabinoid-Related Compounds for Medical Use)

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17 pages, 8184 KiB

Open AccessArticle

Docking and Molecular Dynamic Investigations of Phenylspirodrimanes as Cannabinoid Receptor-2 Agonists

by Abdelsattar M. Omar, Anfal S. Aljahdali, Martin K. Safo, Gamal A. Mohamed and Sabrin R. M. Ibrahim

Molecules 2023, 28(1), 44; https://doi.org/10.3390/molecules28010044 - 21 Dec 2022

Cited by 9 | Viewed by 2114

Abstract

Cannabinoid receptor ligands are renowned as being therapeutically crucial for treating diverse health disorders. Phenylspirodrimanes are meroterpenoids with unique and varied structural scaffolds, which are mainly reported from the Stachybotrys genus and display an array of bioactivities. In this work, 114 phenylspirodrimanes reported from Stachybotrys chartarum were screened for their CB2 agonistic potential using docking and molecular dynamic simulation studies. Compound 56 revealed the highest docking score (−11.222 kcal/mol) compared to E3R_6KPF (native agonist, gscore value −12.12 kcal/mol). The molecular docking and molecular simulation results suggest that compound 56 binds to the putative binding site in the CB2 receptor with good affinity involving key interacting amino acid residues similar to that of the native ligands, E3R. The molecular interactions displayed π–π stacking with Phe183 and hydrogen bond interactions with Thr114, Leu182, and Ser285. These findings identified the structural features of these metabolites that might lead to the design of selective novel ligands for CB2 receptors. Additionally, phenylspirodrimanes should be further investigated for their potential as a CB2 ligand. Full article

(This article belongs to the Special Issue Cannabinoid-Related Compounds for Medical Use)

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20 pages, 2223 KiB

Open AccessArticle

Microwave- and Ultrasound-Assisted Extraction of Cannabinoids and Terpenes from Cannabis Using Response Surface Methodology

by Philip Wiredu Addo, Sai Uday Kumar Reddy Sagili, Samuel Eichhorn Bilodeau, Frederick-Alexandre Gladu-Gallant, Douglas A. MacKenzie, Jennifer Bates, Garnet McRae, Sarah MacPherson, Maxime Paris, Vijaya Raghavan, Valérie Orsat and Mark Lefsrud

Molecules 2022, 27(24), 8803; https://doi.org/10.3390/molecules27248803 - 12 Dec 2022

Cited by 9 | Viewed by 3265

Abstract

Limited studies have explored different extraction techniques that improve cannabis extraction with scale-up potential. Ultrasound-assisted and microwave-assisted extraction were evaluated to maximize the yield and concentration of cannabinoids and terpenes. A central composite rotatable design was used to optimize independent factors (sample-to-solvent ratio, extraction time, extraction temperature, and duty cycle). The optimal conditions for ultrasound- and microwave-assisted extraction were the sample-to-solvent ratios of 1:15 and 1:14.4, respectively, for 30 min at 60 °C. Ultrasound-assisted extraction yielded 14.4% and 14.2% more oil and terpenes, respectively, compared with microwave-assisted extracts. Ultrasound-assisted extraction increased cannabinoid concentration from 13.2–39.2%. Considering reference ground samples, tetrahydrocannabinolic acid increased from 17.9 (g 100 g dry matter⁻¹) to 28.5 and 20 with extraction efficiencies of 159.2% and 111.4% for ultrasound-assisted and microwave-assisted extraction, respectively. Principal component analyses indicate that the first two principal components accounted for 96.6% of the total variance (PC1 = 93.2% and PC2 = 3.4%) for ultrasound-assisted extraction and 92.4% of the total variance (PC1 = 85.4% and PC2 = 7%) for microwave-assisted extraction. Sample-to-solvent ratios significantly (p < 0.05) influenced the secondary metabolite profiles and yields for ultrasound-assisted extracts, but not microwave-assisted extracts. Full article

(This article belongs to the Special Issue Cannabinoid-Related Compounds for Medical Use)

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17 pages, 1201 KiB

Open AccessArticle

Cold Ethanol Extraction of Cannabinoids and Terpenes from Cannabis Using Response Surface Methodology: Optimization and Comparative Study

Molecules 2022, 27(24), 8780; https://doi.org/10.3390/molecules27248780 - 11 Dec 2022

Cited by 9 | Viewed by 4474

Abstract

Efficient cannabis biomass extraction can increase yield while reducing costs and minimizing waste. Cold ethanol extraction was evaluated to maximize yield and concentrations of cannabinoids and terpenes at different temperatures. Central composite rotatable design was used to optimize two independent factors: sample-to-solvent ratio (1:2.9 to 1:17.1) and extraction time (5.7 min–34.1 min). With response surface methodology, predicted optimal conditions at different extraction temperatures were a cannabis-to-ethanol ratio of 1:15 and a 10 min extraction time. With these conditions, yields (g 100 g dry matter⁻¹) were 18.2, 19.7, and 18.5 for −20 °C, −40 °C and room temperature, respectively. Compared to the reference ground sample, tetrahydrocannabinolic acid changed from 17.9 (g 100 g dry matter⁻¹) to 15, 17.5, and 18.3 with an extraction efficiency of 83.6%, 97.7%, 102.1% for −20 °C, −40 °C, and room temperature, respectively. Terpene content decreased by 54.1% and 32.2% for extraction at −20 °C and room temperature, respectively, compared to extraction at −40 °C. Principal component analysis showed that principal component 1 and principal component 2 account for 88% and 7.31% of total variance, respectively, although no significant differences in cold ethanol extraction at different temperatures were observed. Full article

(This article belongs to the Special Issue Cannabinoid-Related Compounds for Medical Use)

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25 pages, 5425 KiB

Open AccessArticle

N-[1,3-Dialkyl(aryl)-2-oxoimidazolidin-4-ylidene]-aryl(alkyl)sulphonamides as Novel Selective Human Cannabinoid Type 2 Receptor (hCB2R) Ligands; Insights into the Mechanism of Receptor Activation/Deactivation

by Eleonora Gianquinto, Federica Sodano, Barbara Rolando, Magdalena Kostrzewa, Marco Allarà, Ali Mokhtar Mahmoud, Poulami Kumar, Francesca Spyrakis, Alessia Ligresti and Konstantin Chegaev

Molecules 2022, 27(23), 8152; https://doi.org/10.3390/molecules27238152 - 23 Nov 2022

Cited by 2 | Viewed by 1846

Abstract

Cannabinoid type 1 (hCB1) and type 2 (hCB2) receptors are pleiotropic and crucial targets whose signaling contributes to physiological homeostasis and its restoration after injury. Being predominantly expressed in peripheral tissues, hCB2R represents a safer therapeutic target than hCB1R, which is highly expressed in the brain, where it regulates processes related to cognition, memory, and motor control. The development of hCB2R ligands represents a therapeutic opportunity for treating diseases such as pain, inflammation and cancer. Identifying new selective scaffolds for cannabinoids and determining the structural determinants responsible for agonism and antagonism are priorities in drug design. In this work, a series of N-[1,3-dialkyl(aryl)-2-oxoimidazolidin-4-ylidene]-aryl(alkyl)sulfonamides is designed and synthesized and their affinity for human hCB1R and hCB2R is determined. Starting with a scaffold selected from the NIH Psychoactive Drug Screening Program Repository, through a combination of molecular modeling and structure–activity relationship studies, we were able to identify the chemical features leading to finely tuned hCB2R selectivity. In addition, an in silico model capable of predicting the functional activity of hCB2R ligands was proposed and validated. The proposed receptor activation/deactivation model enabled the identification of four pure hCB2R-selective agonists that can be used as a starting point for the development of more potent ligands. Full article

(This article belongs to the Special Issue Cannabinoid-Related Compounds for Medical Use)

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16 pages, 2673 KiB

Open AccessArticle

Analysis of Anti-Cancer and Anti-Inflammatory Properties of 25 High-THC Cannabis Extracts

by Dongping Li, Yaroslav Ilnytskyy, Esmaeel Ghasemi Gojani, Olga Kovalchuk and Igor Kovalchuk

Molecules 2022, 27(18), 6057; https://doi.org/10.3390/molecules27186057 - 16 Sep 2022

Cited by 11 | Viewed by 6606

Abstract

Cannabis sativa is one of the oldest cultivated plants. Many of the medicinal properties of cannabis are known, although very few cannabis-based formulations became prescribed drugs. Previous research demonstrated that cannabis varieties are very different in their medicinal properties, likely due to the entourage effect—the synergistic or antagonistic effect of various cannabinoids and terpenes. In this work, we analyzed 25 cannabis extracts containing high levels of delta-9-tetrahydrocannabinol (THC). We used HCC1806 squamous cell carcinoma and demonstrated various degrees of efficiency of the tested extracts, from 66% to 92% of growth inhibition of cancer cells. Inflammation was tested by induction of inflammation with TNF-α/IFN-γ in WI38 human lung fibroblasts. The efficiency of the extracts was tested by analyzing the expression of COX2 and IL6; while some extracts aggravated inflammation by increasing the expression of COX2/IL6 by 2-fold, other extracts decreased inflammation, reducing expression of cytokines by over 5-fold. We next analyzed the level of THC, CBD, CBG and CBN and twenty major terpenes and performed clustering and association analysis between the chemical composition of the extracts and their efficiency in inhibiting cancer growth and curbing inflammation. A positive correlation was found between the presence of terpinene (pval = 0.002) and anti-cancer property; eucalyptol came second, with pval of 0.094. p-cymene and β-myrcene positively correlated with the inhibition of IL6 expression, while camphor correlated negatively. No significant correlation was found for COX2. We then performed a correlation analysis between cannabinoids and terpenes and found a positive correlation for the following pairs: α-pinene vs. CBD, p-cymene vs. CBGA, terpenolene vs. CBGA and isopulegol vs. CBGA. Our work, thus, showed that most of high-THC extracts demonstrate anti-cancer activity, while only certain selected extracts showed anti-inflammatory activity. Presence of certain terpenes, such as terpinene, eucalyptol, cymene, myrcene and camphor, appear to have modulating effects on the activity of cannabinoids. Full article

(This article belongs to the Special Issue Cannabinoid-Related Compounds for Medical Use)

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16 pages, 5865 KiB

Open AccessArticle

Cannabidiol Promotes Neuronal Differentiation Using Akt and Erk Pathways Triggered by Cb1 Signaling

by Santino Blando, Ivana Raffaele, Luigi Chiricosta, Andrea Valeri, Agnese Gugliandolo, Serena Silvestro, Federica Pollastro and Emanuela Mazzon

Molecules 2022, 27(17), 5644; https://doi.org/10.3390/molecules27175644 - 1 Sep 2022

Cited by 6 | Viewed by 2508

Abstract

Recently, the scientific community has started to focus on the neurogenic potential of cannabinoids. The phytocompound cannabidiol (CBD) shows different mechanism of signaling on cannabinoid receptor 1 (CB1), depending on its concentration. In this study, we investigated if CBD may induce in vitro neuronal differentiation after treatment at 5 µM and 10 µM. For this purpose, we decided to use the spinal cord × neuroblastoma hybrid cell line (NSC-34) because of its proliferative and undifferentiated state. The messenger RNAs (mRNAs) expression profiles were tested using high-throughput sequencing technology and Western blot assay was used to determine the number of main proteins in different pathways. Interestingly, the treatment shows different genes associated with neurodifferentiation statistically significant, such as Rbfox3, Tubb3, Pax6 and Eno2. The CB1 signaling pathway is responsible for neuronal differentiation at 10 µM, as suggested by the presence of p-ERK and p-AKT, but not at 5 µM. A new correlation between CBD, neurodifferentiation and retinoic acid receptor-related orphan receptors (RORs) has been observed. Full article

(This article belongs to the Special Issue Cannabinoid-Related Compounds for Medical Use)

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Review

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17 pages, 1655 KiB

Open AccessReview

Cannabis Bioactive Compound-Based Formulations: New Perspectives for the Management of Orofacial Pain

by Giuseppina Crescente, Giuseppe Minervini, Carmela Spagnuolo and Stefania Moccia

Molecules 2023, 28(1), 106; https://doi.org/10.3390/molecules28010106 - 23 Dec 2022

Cited by 43 | Viewed by 3586

Abstract

The management of orofacial pain to alleviate the quality of life of affected patients is becoming increasingly challenging for scientific research and healthcare professionals. From this perspective, in addition to conventional therapies, new alternatives are being sought, increasingly looking at the use of both natural and synthetic products. Cannabis sativa L. represents an interesting source of bioactive compounds, including non-psychoactive cannabinoids, flavonoids, and terpenes, many of which are effective in improving pain intensity. Here, we aim to analyze the possible mechanisms of action of the bioactive natural and synthetic hemp-derived compounds responsible for the modulatory effects on pain-related pathways. The ability of these compounds to act on multiple mechanisms through a synergistic effect, reducing both the release of inflammatory mediators and regulating the response of the endocannabinoid system, makes them interesting agents for alternative formulations to be used in orofacial pain. Full article

(This article belongs to the Special Issue Cannabinoid-Related Compounds for Medical Use)

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