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Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights...
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Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 30 April 2024 | Viewed by 8052

Special Issue Editor

Dr. Uwe M. Grether

E-Mail Website
Guest Editor
Medicinal Chemistry, F. Hoffmann-La Roche AG, Basel, Switzerland
Interests: medicinal chemistry; chemical biology; endocannabinoid system; inflammation; neurodegenerative diseases

Special Issue Information

Dear Colleagues,

The endocannabinoid system (ECS) is an important lipid signaling system ubiquitous to all vertebrates, and is involved in mediating key processes of central and peripheral diseases, including chronic pain, multiple sclerosis, Alzheimer’s disease, obesity, diabetes, and kidney diseases, all of which cause a significant health and socioeconomic burden. The ECS’s key elements include lipid signaling molecules termed ‘endocannabinoids’, their respective receptors, biosynthetic as well as hydrolytic enzymes, and transporters. In particular, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) hold great therapeutic potential. While Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prominent plant-derived cannabinoids, numerous further phytocannabinoids and synthetic ligands targeting CB1R and CB2R have been identified and generated within recent decades. Although multiple of these ligands have been evaluated in humans, clinical success is still limited. Recent developments, including the generation of CB1R and CB2R 3D structures, the identification of allosteric binding pockets, the synthesis of organ-system-selective ligands, a better understanding of biased signaling, and mechanisms of action, could facilitate the design of next-generation drugs, thus, unlocking the receptors’ full therapeutic potential. In this Special Issue of Pharmaceuticals, authors are invited to submit original and review articles covering preclinical and clinical findings enhancing the chance of clinical success of CB1R and CB2R therapies. The proposed topics can cover novel ligands, chemical probes, and mechanistic, translational and biomarker in vitro and in vivo studies. We look forward to your valuable contributions.

Dr. Uwe M. Grether
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • endocannabinoid system (ECS)
  • cannabinoid receptor type 1 (CB1R)
  • cannabinoid receptor type 2 (CB2R)
  • cannabinoids
  • ligand

Published Papers (5 papers)

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Research

20 pages, 9893 KiB  
Article
Evaluating Fatty Acid Amide Hydrolase as a Suitable Target for Sleep Promotion in a Transgenic TauP301S Mouse Model of Neurodegeneration
by Shenée C. Martin, Kathryn K. Joyce, Kathryn M. Harper, Samuel J. Harp, Todd J. Cohen, Sheryl S. Moy and Graham H. Diering
Pharmaceuticals 2024, 17(3), 319; https://doi.org/10.3390/ph17030319 - 29 Feb 2024
Viewed by 806
Abstract
Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer’s disease (AD). Sleep disruption has been demonstrated as a driver of AD pathology and cognitive decline. Therefore, treatments designed to maintain sleep may be effective in slowing or halting AD [...] Read more.
Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer’s disease (AD). Sleep disruption has been demonstrated as a driver of AD pathology and cognitive decline. Therefore, treatments designed to maintain sleep may be effective in slowing or halting AD progression. However, commonly used sleep aid medications are associated with an increased risk of AD, highlighting the need for sleep aids with novel mechanisms of action. The endocannabinoid system holds promise as a potentially effective and novel sleep-enhancing target. By using pharmacology and genetic knockout strategies, we evaluated fatty acid amide hydrolase (FAAH) as a therapeutic target to improve sleep and halt disease progression in a transgenic Tau P301S (PS19) model of Tauopathy and AD. We have recently shown that PS19 mice exhibit sleep disruption in the form of dark phase hyperarousal as an early symptom that precedes robust Tau pathology and cognitive decline. Acute FAAH inhibition with PF3845 resulted in immediate improvements in sleep behaviors in male and female PS19 mice, supporting FAAH as a potentially suitable sleep-promoting target. Moreover, sustained drug dosing for 5–10 days resulted in maintained improvements in sleep. To evaluate the effect of chronic FAAH inhibition as a possible therapeutic strategy, we generated FAAH−/− PS19 mice models. Counter to our expectations, FAAH knockout did not protect PS19 mice from progressive sleep loss, neuroinflammation, or cognitive decline. Our results provide support for FAAH as a novel target for sleep-promoting therapies but further indicate that the complete loss of FAAH activity may be detrimental. Full article
(This article belongs to the Special Issue Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success)
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18 pages, 6272 KiB  
Article
Determination of the Cannabinoid CB1 Receptor’s Positive Allosteric Modulator Binding Site through Mutagenesis Studies
by Hayley M. Green, Daniel M. J. Fellner, David B. Finlay, Daniel P. Furkert and Michelle Glass
Pharmaceuticals 2024, 17(2), 154; https://doi.org/10.3390/ph17020154 - 24 Jan 2024
Viewed by 1000
Abstract
Positive allosteric modulators (PAMs) of the cannabinoid CB1 receptor (CB1) offer potential therapeutic advantages in the treatment of neuropathic pain and addiction by avoiding the adverse effects associated with orthosteric CB1 activation. Here, molecular modeling and mutagenesis were used to [...] Read more.
Positive allosteric modulators (PAMs) of the cannabinoid CB1 receptor (CB1) offer potential therapeutic advantages in the treatment of neuropathic pain and addiction by avoiding the adverse effects associated with orthosteric CB1 activation. Here, molecular modeling and mutagenesis were used to identify residues central to PAM activity at CB1. Six putative allosteric binding sites were identified in silico, including novel sites previously associated with cholesterol binding, and key residues within each site were mutated to alanine. The recently determined ZCZ011 binding site was found to be essential for allosteric agonism, as GAT228, GAT229 and ZCZ011 all increased wild-type G protein dissociation in the absence of an orthosteric ligand; activity that was abolished in mutants F191A3.27 and I169A2.56. PAM activity was demonstrated for ZCZ011 in the presence of the orthosteric ligand CP55940, which was only abolished in I169A2.56. In contrast, the PAM activity of GAT229 was reduced for mutants R220A3.56, L404A8.50, F191A3.27 and I169A2.56. This indicates that allosteric modulation may represent the net effect of binding at multiple sites, and that allosteric agonism is likely to be mediated via the ZCZ011 site. This study underlines the need for detailed understanding of ligand receptor interactions in the search for pure CB1 allosteric modulators. Full article
(This article belongs to the Special Issue Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success)
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14 pages, 5369 KiB  
Article
Computational and Experimental Drug Repurposing of FDA-Approved Compounds Targeting the Cannabinoid Receptor CB1
by Emanuele Criscuolo, Maria Laura De Sciscio, Angela De Cristofaro, Catalin Nicoara, Mauro Maccarrone and Filomena Fezza
Pharmaceuticals 2023, 16(12), 1678; https://doi.org/10.3390/ph16121678 - 02 Dec 2023
Viewed by 1061
Abstract
The cannabinoid receptor 1 (CB1R) plays a pivotal role in regulating various physiopathological processes, thus positioning itself as a promising and sought-after therapeutic target. However, the search for specific and effective CB1R ligands has been challenging, prompting the exploration of drug repurposing (DR) [...] Read more.
The cannabinoid receptor 1 (CB1R) plays a pivotal role in regulating various physiopathological processes, thus positioning itself as a promising and sought-after therapeutic target. However, the search for specific and effective CB1R ligands has been challenging, prompting the exploration of drug repurposing (DR) strategies. In this study, we present an innovative DR approach that combines computational screening and experimental validation to identify potential Food and Drug Administration (FDA)-approved compounds that can interact with the CB1R. Initially, a large-scale virtual screening was conducted using molecular docking simulations, where a library of FDA-approved drugs was screened against the CB1R’s three-dimensional structures. This in silico analysis allowed us to prioritize compounds based on their binding affinity through two different filters. Subsequently, the shortlisted compounds were subjected to in vitro assays using cellular and biochemical models to validate their interaction with the CB1R and determine their functional impact. Our results reveal FDA-approved compounds that exhibit promising interactions with the CB1R. These findings open up exciting opportunities for DR in various disorders where CB1R signaling is implicated. In conclusion, our integrated computational and experimental approach demonstrates the feasibility of DR for discovering CB1R modulators from existing FDA-approved compounds. By leveraging the wealth of existing pharmacological data, this strategy accelerates the identification of potential therapeutics while reducing development costs and timelines. The findings from this study hold the potential to advance novel treatments for a range of CB1R -associated diseases, presenting a significant step forward in drug discovery research. Full article
(This article belongs to the Special Issue Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success)
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20 pages, 2693 KiB  
Article
The Use of CBD and Its Synthetic Analog HU308 in HIV-1-Infected Myeloid Cells
by Anastasia Williams, Pooja Khatkar, Heather Branscome, Yuriy Kim, James Erickson, Mohammad-Ali Jenabian, Cecilia T. Costiniuk and Fatah Kashanchi
Pharmaceuticals 2023, 16(8), 1147; https://doi.org/10.3390/ph16081147 - 12 Aug 2023
Viewed by 1647
Abstract
Currently, there is no cure for human immunodeficiency virus type 1 (HIV-1) infection. However, combined antiretroviral therapy (cART) aids in viral latency and prevents the progression of HIV-1 infection into acquired immunodeficiency syndrome (AIDS). cART has extended many lives, but people living with [...] Read more.
Currently, there is no cure for human immunodeficiency virus type 1 (HIV-1) infection. However, combined antiretroviral therapy (cART) aids in viral latency and prevents the progression of HIV-1 infection into acquired immunodeficiency syndrome (AIDS). cART has extended many lives, but people living with HIV-1 (PLWH) face lifelong ailments such as HIV-associated neurocognitive disorders (HAND) that range from asymptomatic HAND to HIV-1-associated dementia. HAND has been attributed to chronic inflammation and low-level infection within the central nervous system (CNS) caused by proinflammatory cytokines and viral products. These molecules are shuttled into the CNS within extracellular vesicles (EVs), lipid bound nanoparticles, and are released from cells as a form of intercellular communication. This study investigates the impact of cannabidiol (CBD), as a promising and potential therapeutic for HAND patients, and a similar synthetic molecule, HU308, on the EVs released from HIV-1-infected myeloid cells as well as HIV-1-infected 3D neurospheres. The data shows that both CBD and HU308 decrease non-coding and coding viral RNA (TAR and env) as well as proinflammatory cytokines as IL-1β and TNF-α mRNA. This decrease in viral RNA occurs in in vitro differentiated primary macrophages, in EVs released from HIV-1-infected cells monocytes, and infected neurospheres. Furthermore, a 3D neurosphere model shows an overall decrease in proinflammatory mRNA with HU308. Finally, using a humanized mouse model of HIV-1 infection, plasma viral RNA was shown to significantly decrease with HU308 alone and was most effective in combination with cART, even when compared to the typical cART treatment. Overall, CBD or HU308 may be a viable option to decrease EV release and associated cytokines which would dampen the virus spread and may be used in effective treatment of HAND in combination with cART. Full article
(This article belongs to the Special Issue Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success)
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Graphical abstract

21 pages, 5423 KiB  
Article
Acute Toxicity and Pharmacokinetic Profile of an EU-GMP-Certified Cannabis sativa L. in Rodents
by Leontina-Elena Filipiuc, Raluca Ştefănescu, Carmen Solcan, Mitică Ciorpac, Andrei Szilagyi, Dana Cojocaru, Gabriela Dumitrita Stanciu, Ioana Creangă, Cătălin-Cezar Caratașu, Daniela-Carmen Ababei, Roxana-Elena Gavrila, Andrei-Daniel Timofte, Silviu-Iulian Filipiuc and Veronica Bild
Pharmaceuticals 2023, 16(5), 694; https://doi.org/10.3390/ph16050694 - 03 May 2023
Cited by 1 | Viewed by 2596
Abstract
The conundrum of Cannabis sativa’s applications for therapeutical purposes is set apart by the hundreds of known and commercially available strains, the social, cultural and historical context, and the legalization of its use for medical purposes in various jurisdictions around the globe. [...] Read more.
The conundrum of Cannabis sativa’s applications for therapeutical purposes is set apart by the hundreds of known and commercially available strains, the social, cultural and historical context, and the legalization of its use for medical purposes in various jurisdictions around the globe. In an era where targeted therapies are continuously being developed and have become the norm, it is imperative to conduct standardized, controlled studies on strains currently cultivated under Good Manufacturing Practices (GMP) certification, a standard that guarantees the quality requirements for modern medical and therapeutic use. Thus, the aim of our study is to evaluate the acute toxicity of a 15.6% THC: <1% CBD, EU-GMP certified, Cannabis sativa L. in rodents, following the OECD acute oral toxicity guidelines, and to provide an overview of its pharmacokinetic profile. Groups of healthy female Sprague-Dawley rats were treated orally with a stepwise incremental dose, each step using three animals. The absence or presence of plant-induced mortality in rats dosed at one step determined the next step. For the EU GMP-certified Cannabis sativa L. investigated, we determined an oral LD50 value of over 5000 mg/kg in rats and a human equivalent oral dose of ≈806.45 mg/kg. Additionally, no significant clinical signs of toxicity or gross pathological findings were observed. According to our data, the toxicology, safety and pharmacokinetic profile of the tested EU-GMP-certified Cannabis sativa L. support further investigations through efficacy and chronic toxicity studies in preparation for potential future clinical applications and especially for the treatment of chronic pain. Full article
(This article belongs to the Special Issue Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

1. Title: Effect of the cannabinoid agonist WIN 55,212-2 on neuropathic and visceral pain induced by a non-diarrheagenic dose of the antitumoral drug 5-fluorouracil in the rat.

Prof. Raquel Abalo Delgado; etc.

Abstract:

5-fluorouracil is an antineoplastic drug frequently used to treat colorectal cancer, but it causes diarrhea and mucositis as relevant side effects. In murine models, it produces enteric neuropathy and gastrointestinal dysmotility. Our aim is to evaluate the effects of the cannabinoid agonist WIN 55,212-2 on neuropathic and visceral pain induced by a non-diarrheagenic dose of 5- fluorouracil in rats. Adult male Wistar rats receiving a dose of 5-fluorouracil (150 mg/kg, ip) or saline were monitored for 15 days. Gastrointestinal function (motility, colonic sensitivity), gut wall structure and tactile sensitivity were evaluated throughout the study. WIN 55,212-2 was administered to evaluate its alleviating effect on somatic (50-100 µg ipl; 1 mg/kg, ip) and visceral (1 mg/kg, ip) hypersensitivity. The cannabinoid tetrad was used to assess the central effects of WIN 55,212-2 (1 mg/kg, ip). 5-fluorouracil acutely decreased food intake and body weight gain and produced mucositis and thermal hyperalgesia, but these effects were reduced afterwards, and were not accompanied by diarrhea. Tactile mechanical allodynia (a sign of somatic peripheral neuropathy) was evident and alleviated by WIN 55,212-2, regardless of the route or dose administered, without causing alterations in the cannabinoid tetrad. Finally, 5-fluorouracil tended to increase the sensitivity to intracolonic mechanical stimulation, whereas WIN 55,212-2 reduced the abdominal contractions induced by increasing intracolonic pressure in both control and 5-fluorouracil-treated animals. The activation of the cannabinoid system at non-psychotropic doses may be useful to alleviate neuropathic and visceral pain associated with antitumoral drug treatments.

 

2. Title: Potential Drug Interactions with Cannabinoids in selected Chronic Diseases: Epilepsy, Autism Spectrum Disorders, Oncology, Multiple Sclerosis and Pain

Maria G. Campos1,2*, Maria China1, Mariana Claudio1, Miguel Capinha1, Rita Torres1, Simão Oliveira1, and Ana Fortuna 1,3,4*

Abstract: The clinical practice implies a research translation that will help the use of scientific data and therapeutic evidence for patient benefits. This review critically summarizes the potential impact of cannabinoids in concomitance with other drugs in chronic diseases that seem to be ameliorated with cannabinoids:  Epilepsy, Autism Spectrum Disorders (ASD), Oncology, Multiple Sclerosis, and Chronic Pain. The potential interactions are able to change the predicted outcomes of therapeutic protocols and need to be evaluated. Some of the effects would be additive or synergistic, antagonistic, but can also enroll changes in absorption, distribution, metabolism, particularly via cytochrome P450 (CYP) isoenzymes (e.g CYP2C9 and CYP3A4) and excretion. For instance, the combination of cannabis-derived compounds and the antifungal drug ketoconazole, a CYP3A4 inhibitor, was reported to increase plasma concentration of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Opposable, rifampicin, a CYP3A4 inducer, stands out for the approximately 20-40% reduction in plasma THC levels and 50% to 60% for CBD. Other CYP3A4 inhibitors and inducers are likely to have a similar effect on plasma concentrations if co-administered. Indeed, pharmacokinetic interactions have been also reported with antiepileptic drugs. Moreover, pharmacodynamic interactions between cannabinoids and drugs with sympathomimetic effects (eg tachycardia, hypertension), central nervous system depressants (eg drowsiness, ataxia), and anticholinergics (eg tachycardia and drowsiness) should also be expected. Even though pending further studies, there is currently clinical evidence supporting drug interaction with cannabinoids, demanding doctors who evaluate the risk of drug combinations with cannabinoids. The tables herein provided were designed to facilitate the identification of biorelevant interactions that may compromise therapeutic efficacy and toxicity.

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