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Endocannabinoid System Modulators in a Medicinal Chemistry Perspective

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 33748

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Special Issue Editors

Dr. Alessandra Bisi

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Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
Interests: flavonoids; drug design; hybrid molecules; MDR reversal; neurodegeneration
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Angela Rampa

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Guest Editor

Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
Interests: drug design; hybrid molecules; Alzheimer’s disease; AChE inhibitors; FAAH inhibitors; CB receptors ligands; flavonoids
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Currently, the term “endocannabinoid system” (ECS) includes endogenous cannabinoids (endocannabinoids, mainly anandamide and 2-arachidonoylglycerol), the enzymes involved in their biosynthesis, transport and degradation and the G protein-coupled receptors (cannabinoid receptors, CBRs) with which they interact. In recent years, it has become clear that the ECS is up-regulated in numerous pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic and cardiovascular diseases, pain and cancer, and that its modulation offers significant potential for intervention in different areas of human health. This Special Issue aims to provide an overview of the latest studies on potential drugs acting on this challenging system, both involving the cannabinoid receptors and/or the enzymes responsible for endocannabinoids transport and hydrolysis, recognized as validated targets in medicinal chemistry.

Prof. Dr. Alessandra Bisi
Prof. Dr. Angela Rampa

Guest Editors

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Keywords

CB ligands
FAAH inhibitors
MAGL inhibitors
Reuptake inhibitors
Neurodegeneration
Pain
Cancer

Published Papers (11 papers)

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Research

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18 pages, 19150 KiB

Open AccessArticle

Zerumbone Ameliorates Neuropathic Pain Symptoms via Cannabinoid and PPAR Receptors Using In Vivo and In Silico Models

by Jasmine Siew Min Chia, Ahmad Akira Omar Farouk, Tengku Azam Shah Tengku Mohamad, Mohd Roslan Sulaiman, Hanis Zakaria, Nurul Izzaty Hassan and Enoch Kumar Perimal

Molecules 2021, 26(13), 3849; https://doi.org/10.3390/molecules26133849 - 24 Jun 2021

Cited by 11 | Viewed by 2329

Abstract

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone’s antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB₁ receptor), SR144528 (CB₂ receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB₁, PPARα and PPARγ in zerumbone’s action against mechanical allodynia, whereas only CB₁ and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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6 pages, 37491 KiB

Open AccessArticle

New Disulfiram Derivatives as MAGL-Selective Inhibitors

by Ziad Omran

Molecules 2021, 26(11), 3296; https://doi.org/10.3390/molecules26113296 - 30 May 2021

Cited by 5 | Viewed by 2441

Abstract

Monoacylglycerol lipase (MAGL) is a key enzyme in the human endocannabinoid system. It is also the main enzyme responsible for the conversion of 2-arachidonoyl glycerol (2-AG) to arachidonic acid (AA), a precursor of prostaglandin synthesis. The inhibition of MAGL activity would be beneficial for the treatment of a wide range of diseases, such as inflammation, neurodegeneration, metabolic disorders and cancer. Here, the author reports the pharmacological evaluation of new disulfiram derivatives as potent inhibitors of MAGL. These analogues displayed high inhibition selectivity over fatty acid amide hydrolase (FAAH), another endocannabinoid-hydrolyzing enzyme. In particular, compound 2i inhibited MAGL in the low micromolar range. However, it did not show any inhibitory activity against FAAH. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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18 pages, 2755 KiB

Open AccessFeature PaperArticle

New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators

by Serena Montanari, Marco Allarà, Laura Scalvini, Magdalena Kostrzewa, Federica Belluti, Silvia Gobbi, Marina Naldi, Silvia Rivara, Manuela Bartolini, Alessia Ligresti, Alessandra Bisi and Angela Rampa

Molecules 2021, 26(11), 3254; https://doi.org/10.3390/molecules26113254 - 28 May 2021

Cited by 7 | Viewed by 2564

Abstract

In the last years, the connection between the endocannabinoid system (eCS) and neuroprotection has been discovered, and evidence indicates that eCS signaling is involved in the regulation of cognitive processes and in the pathophysiology of Alzheimer’s disease (AD). Accordingly, pharmacotherapy targeting eCS could represent a valuable contribution in fighting a multifaceted disease such as AD, opening a new perspective for the development of active agents with multitarget potential. In this paper, a series of coumarin-based carbamic and amide derivatives were designed and synthesized as multipotent compounds acting on cholinergic system and eCS-related targets. Indeed, they were tested with appropriate enzymatic assays on acetyl and butyryl-cholinesterases and on fatty acid amide hydrolase (FAAH), and also evaluated as cannabinoid receptor (CB1 and CB2) ligands. Moreover, their ability to reduce the self-aggregation of beta amyloid protein (Aβ₄₂) was assessed. Compounds 2 and 3, bearing a carbamate function, emerged as promising inhibitors of hAChE, hBuChE, FAAH and Aβ₄₂ self-aggregation, albeit with moderate potencies, while the amide 6 also appears a promising CB1/CB2 receptors ligand. These data prove for the new compounds an encouraging multitarget profile, deserving further evaluation. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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11 pages, 4863 KiB

Open AccessArticle

Neuroprotection with the Cannabidiol Quinone Derivative VCE-004.8 (EHP-101) against 6-Hydroxydopamine in Cell and Murine Models of Parkinson’s Disease

by Sonia Burgaz, Concepción García, María Gómez-Cañas, Alain Rolland, Eduardo Muñoz and Javier Fernández-Ruiz

Molecules 2021, 26(11), 3245; https://doi.org/10.3390/molecules26113245 - 28 May 2021

Cited by 13 | Viewed by 3155

Abstract

The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson’s disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome proliferator-activated receptor-γ (PPAR-γ) and possibly other pathways. In the present study, we investigated VCE-004.8 (formulated as EHP-101 for oral administration), the 3-hydroxyquinone derivative of cannabidiol (CBD), with agonist activity at the cannabinoid receptor type-2 (CB₂) receptor in addition to its activity at the PPAR-γ receptor. Studies were conducted in both in vivo (lesioned-mice) and in vitro (SH-SY5Y cells) models using the classic parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). Our data confirmed that the treatment with VCE-004.8 partially reduced the loss of tyrosine hydroxylase (TH)-positive neurons measured in the substantia nigra of 6-OHDA-lesioned mice, in parallel with an almost complete reversal of the astroglial (GFAP) and microglial (CD68) reactivity occurring in this structure. Such neuroprotective effects attenuated the motor deficiencies shown by 6-OHDA-lesioned mice in the cylinder rearing test, but not in the pole test. Next, we explored the mechanism involved in the beneficial effect of VCE-004.8 in vivo, by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-004.8 at a concentration of 10 µM, which was completely reversed by the addition of antagonists, T0070907 and SR144528, aimed at blocking PPAR-γ and CB₂ receptors, respectively. The treatment with T0070907 alone only caused a partial reversal, whereas SR144528 alone had no effect, indicating a major contribution of PPAR-γ receptors in the cytoprotective effect of VCE-004.8 at 10 µM. In summary, our data confirmed the neuroprotective potential of VCE-004.8 in 6-OHDA-lesioned mice, and in vitro studies confirmed a greater relevance for PPAR-γ receptors rather than CB₂ receptors in these effects. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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8 pages, 1192 KiB

Open AccessArticle

Contrasting Roles of Ang II and ACEA in the Regulation of IL10 and IL1β Gene Expression in Primary SHR Astroglial Cultures

by Dhanush Haspula and Michelle A. Clark

Molecules 2021, 26(10), 3012; https://doi.org/10.3390/molecules26103012 - 19 May 2021

Cited by 3 | Viewed by 1860

Abstract

Angiotensin (Ang) II is well-known to have potent pro-oxidant and pro-inflammatory effects in the brain. Extensive crosstalk between the primary Ang II receptor, Ang type 1 receptor (AT1R), and the cannabinoid type 1 receptor (CB1R) has been demonstrated by various groups in the last decade. Since activation of glial CB1R has been demonstrated to play a key role in the resolution of inflammatory states, we investigated the role of Ang II (100 nM) and/or ACEA (10 nM), a potent CB1R-specific agonist in the regulation of inflammatory markers in astrocytes from spontaneously hypertensive rats (SHR) and Wistar rats. Astrocytes were cultured from brainstems and cerebellums of SHR and Wistar rats and assayed for IL1β and IL10 gene expression and secreted fraction, in treated and non-treated cells, by employing qPCR and ELISA, respectively. mRNA expression of both IL10 and IL1β were significantly elevated in untreated brainstem and cerebellar astrocytes isolated from SHR when compared to Wistar astrocytes. No changes were observed in the secreted fraction. While ACEA-treatment resulted in a significant increase in IL10 gene expression in Wistar brainstem astrocytes (Log2FC ≥ 1, p < 0.05), its effect in SHR brainstem astrocytes was diminished. Ang II treatment resulted in a strong inhibitory effect on IL10 gene expression in astrocytes from both brain regions of SHR and Wistar rats (Log2FC ≤ −1, p < 0.05), and an increase in IL1β gene expression in brainstem astrocytes from both strains (Log2FC ≥ 1, p < 0.05). Co-treatment of Ang II and ACEA resulted in neutralization of Ang II-mediated effect in Wistar brainstem and cerebellar astrocytes, but not SHR astrocytes. Neither Ang II nor ACEA resulted in any significant changes in IL10 or IL1β secreted proteins. These data suggest that Ang II and ACEA have opposing roles in the regulation of inflammatory gene signature in astrocytes isolated from SHR and Wistar rats. This however does not translate into changes in their secreted fractions. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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21 pages, 5810 KiB

Open AccessFeature PaperArticle

Allosteric Modulation of the CB1 Cannabinoid Receptor by Cannabidiol—A Molecular Modeling Study of the N-Terminal Domain and the Allosteric-Orthosteric Coupling

by Jakub Jakowiecki, Renata Abel, Urszula Orzeł, Paweł Pasznik, Robert Preissner and Sławomir Filipek

Molecules 2021, 26(9), 2456; https://doi.org/10.3390/molecules26092456 - 23 Apr 2021

Cited by 16 | Viewed by 3526

Abstract

The CB₁ cannabinoid receptor (CB₁R) contains one of the longest N termini among class A G protein-coupled receptors. Mutagenesis studies suggest that the allosteric binding site of cannabidiol (CBD) involves residues from the N terminal domain. In order to study the allosteric binding of CBD to CB₁R we modeled the whole N-terminus of this receptor using the replica exchange molecular dynamics with solute tempering (REST2) approach. Then, the obtained structures of CB₁R with the N terminus were used for ligand docking. A natural cannabinoid receptor agonist, Δ⁹-THC, was docked to the orthosteric site and a negative allosteric modulator, CBD, to the allosteric site positioned between extracellular ends of helices TM1 and TM2. The molecular dynamics simulations were then performed for CB₁R with ligands: (i) CBD together with THC, and (ii) THC-only. Analyses of the differences in the residue-residue interaction patterns between those two cases allowed us to elucidate the allosteric network responsible for the modulation of the CB₁R by CBD. In addition, we identified the changes in the orthosteric binding mode of Δ⁹-THC, as well as the changes in its binding energy, caused by the CBD allosteric binding. We have also found that the presence of a complete N-terminal domain is essential for a stable binding of CBD in the allosteric site of CB₁R as well as for the allosteric-orthosteric coupling mechanism. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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19 pages, 1705 KiB

Open AccessArticle

Traumatic Stress, Chronic Ethanol Exposure, or the Combination, Alter Cannabinoid System Components in Reward and Limbic Regions of the Mouse Brain

by Veronica M. Piggott, Scott C. Lloyd, James I. Matchynski, Shane A. Perrine and Alana C. Conti

Molecules 2021, 26(7), 2086; https://doi.org/10.3390/molecules26072086 - 06 Apr 2021

Cited by 5 | Viewed by 2280

Abstract

The cannabinoid system is independently affected by stress and chronic ethanol exposure. However, the extent to which co-occurrence of traumatic stress and chronic ethanol exposure modulates the cannabinoid system remains unclear. We examined levels of cannabinoid system components, anandamide, 2-arachidonoylglycerol, fatty acid amide hydrolase, and monoacylglycerol lipase after mouse single-prolonged stress (mSPS) or non-mSPS (Control) exposure, with chronic intermittent ethanol (CIE) vapor or without CIE vapor (Air) across several brain regions using ultra-high-performance liquid chromatography tandem mass spectrometry or immunoblotting. Compared to mSPS-Air mice, anandamide and 2-arachidonoylglycerol levels in the anterior striatum were increased in mSPS-CIE mice. In the dorsal hippocampus, anandamide content was increased in Control-CIE mice compared to Control-Air, mSPS-Air, or mSPS-CIE mice. Finally, amygdalar anandamide content was increased in Control-CIE mice compared to Control-Air, or mSPS-CIE mice, but the anandamide content was decreased in mSPS-CIE compared to mSPS-Air mice. Based on these data we conclude that the effects of combined traumatic stress and chronic ethanol exposure on the cannabinoid system in reward pathway regions are driven by CIE exposure and that traumatic stress affects the cannabinoid components in limbic regions, warranting future investigation of neurotherapeutic treatment to attenuate these effects. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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16 pages, 1318 KiB

Open AccessArticle

Cannabinoid Quinones—A Review and Novel Observations

by Natalya M. Kogan, Maximilian Peters and Raphael Mechoulam

Molecules 2021, 26(6), 1761; https://doi.org/10.3390/molecules26061761 - 21 Mar 2021

Cited by 15 | Viewed by 4101

Abstract

A cannabinoid anticancer para-quinone, HU-331, which was synthesized by our group five decades ago, was shown to have very high efficacy against human cancer cell lines in-vitro and against in-vivo grafts of human tumors in nude mice. The main mechanism was topoisomerase IIα catalytic inhibition. Later, several groups synthesized related compounds. In the present presentation, we review the publications on compounds synthesized on the basis of HU-331, summarize their published activities and mechanisms of action and report the synthesis and action of novel quinones, thus expanding the structure-activity relationship in these series. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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14 pages, 1356 KiB

Open AccessArticle

Cannabinoid Receptor Modulation of Neurogenesis: ST14A Striatal Neural Progenitor Cells as a Simplified In Vitro Model

by Erika Cottone, Valentina Pomatto, Stefania Rapelli, Rosaria Scandiffio, Ken Mackie and Patrizia Bovolin

Molecules 2021, 26(5), 1448; https://doi.org/10.3390/molecules26051448 - 07 Mar 2021

Cited by 6 | Viewed by 1934

Abstract

The endocannabinoid system (ECS) is involved in the modulation of several basic biological processes, having widespread roles in neurodevelopment, neuromodulation, immune response, energy homeostasis and reproduction. In the adult central nervous system (CNS) the ECS mainly modulates neurotransmitter release, however, a substantial body of evidence has revealed a central role in regulating neurogenesis in developing and adult CNS, also under pathological conditions. Due to the complexity of investigating ECS functions in neural progenitors in vivo, we tested the suitability of the ST14A striatal neural progenitor cell line as a simplified in vitro model to dissect the role and the mechanisms of ECS-regulated neurogenesis, as well as to perform ECS-targeted pharmacological approaches. We report that ST14A cells express various ECS components, supporting the presence of an active ECS. While CB1 and CB2 receptor blockade did not affect ST14A cell number, exogenous administration of the endocannabinoid 2-AG and the synthetic CB2 agonist JWH133 increased ST14A cell proliferation. Phospholipase C (PLC), but not PI3K pharmacological blockade negatively modulated CB2-induced ST14A cell proliferation, suggesting that a PLC pathway is involved in the steps downstream to CB2 activation. On the basis of our results, we propose ST14A neural progenitor cells as a useful in vitro model for studying ECS modulation of neurogenesis, also in prospective in vivo pharmacological studies. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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Review

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22 pages, 8930 KiB

Open AccessReview

Tricyclic Pyrazole-Based Compounds as Useful Scaffolds for Cannabinoid CB₁/CB₂ Receptor Interaction

by Battistina Asproni, Gabriele Murineddu, Paola Corona and Gérard A. Pinna

Molecules 2021, 26(8), 2126; https://doi.org/10.3390/molecules26082126 - 07 Apr 2021

Cited by 4 | Viewed by 2025

Abstract

Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB₁ and/or CB₂ receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB₁ antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB₁ or CB₂ receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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11 pages, 1584 KiB

Open AccessReview

Endocannabinoid System Dysregulation from Acetaminophen Use May Lead to Autism Spectrum Disorder: Could Cannabinoid Treatment Be Efficacious?

by Stephen Schultz, Georgianna G. Gould, Nicola Antonucci, Anna Lisa Brigida and Dario Siniscalco

Molecules 2021, 26(7), 1845; https://doi.org/10.3390/molecules26071845 - 25 Mar 2021

Cited by 6 | Viewed by 6277

Abstract

Persistent deficits in social communication and interaction, and restricted, repetitive patterns of behavior, interests or activities, are the core items characterizing autism spectrum disorder (ASD). Strong inflammation states have been reported to be associated with ASD. The endocannabinoid system (ECS) may be involved in ASD pathophysiology. This complex network of lipid signaling pathways comprises arachidonic acid and 2-arachidonoyl glycerol-derived compounds, their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. Alterations of the ECS have been reported in both the brain and the immune system of ASD subjects. ASD children show low EC tone as indicated by low blood levels of endocannabinoids. Acetaminophen use has been reported to be associated with an increased risk of ASD. This drug can act through the ECS to produce analgesia. It may be that acetaminophen use in children increases the risk for ASD by interfering with the ECS.This mini-review article summarizes the current knowledge on this topic. Full article

(This article belongs to the Special Issue Endocannabinoid System Modulators in a Medicinal Chemistry Perspective)

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