Tag Archives: antagonists

Inhibition of Cannabinoid Receptor 1 Can Influence the Lipid Metabolism in Mice with Diet-Induced Obesity.

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“A growing number of evidences accumulated about critical metabolic role of cannabinoid type 1 receptor (CB1), carnitine palmitoyltransferase-1 (CPT1) and peroxisome proliferator-activated receptors (PPARs) in some peripheral tissues, including adipose tissue, liver, skeletal muscle and heart.

Taken together, these data indicate that the inhibition of CB1 could ameliorate lipid metabolism via the stimulation of the CPT1A and CPT1B expression in vivo. Simultaneously, the PPARα and PPARγ expression levels significantly differed compared to that of PPARβ in obesity and lipid metabolism-related disorders under blockade of CB1.

Both the mechanism of the influence of CB1 inhibition on lipid metabolism in the examined tissues and the specific mechanism of PPARα, PPARγ and PPARβ involvement in lipid exchange under these conditions remain to be further elucidated.”

https://www.ncbi.nlm.nih.gov/pubmed/30472964

https://link.springer.com/article/10.1134%2FS0006297918100127

Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells.

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“Neuroinflammation plays a vital role in Alzheimer’s disease and other neurodegenerative conditions.

The orphan G-protein-coupled receptor 55 (GPR55) has been reported to modulate inflammation and is expressed in immune cells such as monocytes and microglia.

Targeting GPR55 might be a new therapeutic option to treat neurodegenerative diseases with a neuroinflammatory background such as Alzheimer’s disease, Parkinson, and multiple sclerosis (MS).”

https://www.ncbi.nlm.nih.gov/pubmed/30453998

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1362-7

“Pharmacological characterization of GPR55, a putative cannabinoid receptor.”  https://www.ncbi.nlm.nih.gov/pubmed/20298715

“Our findings also suggest that GPR55 may be a new pharmacological target for the following C. sativa constituents: Δ9-THCV, CBDV, CBGA, and CBGV. These Cannabis sativa constituents may represent novel therapeutics targeting GPR55.”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249141/

Cannabinoids for Treating Cardiovascular Disorders: Putting Together a Complex Puzzle.

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“Cannabinoids have been increasingly gaining attention for their therapeutic potential in treating various cardiovascular disorders. These disorders include myocardial infarction, hypertension, atherosclerosis, arrhythmias, and metabolic disorders.

The aim of this review is to cover the main actions of cannabinoids on the cardiovascular system by examining the most recent advances in this field and major literature reviews.

It is well recognized that the actions of cannabinoids are mediated by either cannabinoid 1 or cannabinoid 2 receptors (CB2Rs). Endocannabinoids produce a triphasic response on blood pressure, while synthetic cannabinoids show a tissue-specific and species-specific response.

Blocking cannabinoid 1 receptors have been shown to be effective against cardiometabolic disorders, although this should be done peripherally. Blocking CB2Rs may be a useful way to treat atherosclerosis by affecting immune cells. The activation of CB2Rs was reported to be useful in animal studies of myocardial infarction and cardiac arrhythmia.

Although cannabinoids show promising effects in animal models, this does not always translate into human studies, and therefore, extensive clinical studies are needed to truly establish their utility in treating cardiovascular disease.”

https://www.ncbi.nlm.nih.gov/pubmed/30464888

Structure-Based Identification of Potent Natural Product Chemotypes as Cannabinoid Receptor 1 Inverse Agonists.

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“Natural products are an abundant source of potential drugs, and their diversity makes them a rich and viable prospective source of bioactive cannabinoid ligands.

Cannabinoid receptor 1 (CB1) antagonists are clinically established and well documented as potential therapeutics for treating obesity, obesity-related cardiometabolic disorders, pain, and drug/substance abuse, but their associated CNS-mediated adverse effects hinder the development of potential new drugs and no such drug is currently on the market. This limitation amplifies the need for new agents with reduced or no CNS-mediated side effects.

We are interested in the discovery of new natural product chemotypes as CB1 antagonists, which may serve as good starting points for further optimization towards the development of CB1 therapeutics.

Most importantly, these bioactive compounds represent structurally new natural product chemotypes in the area of cannabinoid research and could be considered for further structural optimization as CB1 ligands.”

https://www.ncbi.nlm.nih.gov/pubmed/30322136

https://www.mdpi.com/1420-3049/23/10/2630

Cannabinoids in depressive disorders.

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 Life Sciences “Cannabis sativa is one of the most popular recreational and medicinal plants. Benefits from use of cannabinoid agents in epilepsy, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and others have been suggested. It seems that the endocannabinoid system is also involved in the pathogenesis and treatment of depression, though its role in this mental disease has not been fully understood yet. Both the pro- and antidepressant activity have been reported after cannabis consumption and a number of pre-clinical studies have demonstrated that both agonist and antagonist of the endocannabinoid receptors act similarly to antidepressants. Responses to the cannabinoid agents are relatively fast, and most probably, the noradrenergic, serotoninergic, glutamatergic neurotransmission, neuroprotective activity, as well as modulation of the hypothalamic-pituitary-adrenal axis are implicated in the observed effects. Based on the published data, the endocannabinoid system evidently gives novel ideas and options in the field of antidepressant treatment, however further studies are needed to determine which group of patients could benefit from this type of therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/30290188

https://www.sciencedirect.com/science/article/pii/S0024320518306040?via%3Dihub

Genetic and pharmacological regulation of the endocannabinoid CB1 receptor in Duchenne muscular dystrophy.

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 Nature Communications

“The endocannabinoid system refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases.

However, the potential role of endocannabinoids in skeletal muscle disorders remains unknown. Here we report the role of the endocannabinoid CB1 receptors in Duchenne’s muscular dystrophy.

In murine and human models, CB1 transcripts show the highest degree of expression at disease onset, and then decline overtime. Similar changes are observed for PAX7, a key regulator of muscle stem cells. Bioinformatics and biochemical analysis reveal that PAX7 binds and upregulates the CB1 gene in dystrophic more than in healthy muscles.

Rimonabant, an antagonist of CB1, promotes human satellite cell differentiation in vitro, increases the number of regenerated myofibers, and prevents locomotor impairment in dystrophic mice.

In conclusion, our study uncovers a PAX7-CB1 cross talk potentially exacerbating DMD and highlights the role of CB1 receptors as target for potential therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/30262909

“We propose that the endocannabinoid system participates in the development of degenerative muscle disease, through effects on muscle differentiation, regeneration, and repair processes, and suggest that CB1 receptor may represent a potential target for the adjuvant therapy of muscle dystrophies.”

https://www.nature.com/articles/s41467-018-06267-1

Exploring the Ligand Efficacy of Cannabinoid Receptor 1 (CB1) using Molecular Dynamics Simulations.

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Scientific Reports

“Cannabinoid receptor 1 (CB1) is a promising therapeutic target for a variety of disorders. Distinct efficacy profiles showed different therapeutic effects on CB1 dependent on three classes of ligands: agonists, antagonists, and inverse agonists. To discriminate the distinct efficacy profiles of the ligands, we carried out molecular dynamics (MD) simulations to identify the dynamic behaviors of inactive and active conformations of CB1 structures with the ligands. In addition, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method was applied to analyze the binding free energy decompositions of the CB1-ligand complexes. With these two methods, we found the possibility that the three classes of ligands can be discriminated. Our findings shed light on the understanding of different efficacy profiles of ligands by analyzing the structural behaviors of intact CB1 structures and the binding energies of ligands, thereby yielding insights that are useful for the design of new potent CB1 drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/30213978

https://www.nature.com/articles/s41598-018-31749-z

“Chemical structure of the partial agonist THC, antagonist THCV, and inverse agonist Taranabant.”

Figure 1

Role of the endocannabinoid system in drug addiction.

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Biochemical Pharmacology

“Drug addiction is a chronic relapsing disorder that produces a dramaticglobal health burden worldwide. Not effective treatment of drug addiction is currently available probably due to the difficulties to find an appropriate target to manage this complex disease raising the needs for further identification of novel therapeutic approaches.

The endocannabinoid system has been found to play a crucial role in the neurobiological substrate underlying drug addiction.

Endocannabinoids and cannabinoid receptors are widely expressed in the main areas of the mesocorticolimbic system that participate in the initiation and maintenance of drug consumption and in the development of compulsion and loss of behavioral control occurring during drug addiction.

The identification of the important role played by CB1 cannabinoid receptors in drug addiction encouraged the possible used of an early commercialized CB1 receptor antagonist for treating drug addiction.

However, the incidence of serious psychiatric adverse events leaded to the sudden withdrawal from the market of this CB1 antagonist and all the research programs developed by pharmaceutical companies to obtain new CB1 antagonists were stopped.

Currently, new research strategies are under development to target the endocannabinoid system for drug addiction avoiding these side effects, which include allosteric negative modulators of CB1 receptors and compounds targeting CB2 receptors.

Recent studies showing the potential role of CB2 receptors in the addictive properties of different drugs of abuse have open a promising research opportunity to develop novel possible therapeutic approaches.”

https://www.ncbi.nlm.nih.gov/pubmed/30217570

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303952

Role of Cannabinoids in Obesity.

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“Obesity is an increasing health problem worldwide. Its related comorbidities imply a high cost for the National Health System and diminish a patient’s life quality.

Adipose tissue is composed of three types of cells. White adipocytes are involved in fat storage and secretion of hormones. Brown adipocytes are involved in thermogenesis and caloric expenditure. Beige adipocytes are transitional adipocytes that in response to various stimuli can turn from white to brown and could be protective against the obesity, enhancing energy expenditure.

The conversion of white in beige adipose tissue is a potential new therapeutic target for obesity.

Cannabinoid receptors (CB) regulate thermogenesis, food intake and inflammation. CB1 ablation or inhibition helps reducing body weight and food intake. Stimulation of CB2 limits inflammation and promotes anti-obesity effects by reducing food intake and weight gain. Its genetic ablation results in adiposity development.

CB receptors are also responsible for transforming white adipose tissue towards beige or brown adipocytes, therefore their modulation can be considered potential anti-obesity target. CB1 principal localization in central nervous system represents an important limit. Stimulation of CB2, principally localized on peripheral cells instead, should facilitate the anti-obesity effects without exerting remarkable psychotropic activity.”

https://www.ncbi.nlm.nih.gov/pubmed/30201891

http://www.mdpi.com/1422-0067/19/9/2690

Cannabinoids and reduced risk of hepatic steatosis in HIV-HCV co-infection: paving the way for future clinical research

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“Whether or not cannabis itself or cannabinoids contained in it may help to reduce hepatic steatosis in HIV-HCV coinfected patients remains an open question. The existing body of knowledge on the interactions between cannabis and the liver suggest a protective effect of cannabinoids on insulin resistance, diabetes, and NAFLD in the general population. Clinical research with randomized study designs is needed to evaluate the efficacy and safety of cannabis-based pharmacotherapies in HIV-HCV coinfected patients. Targeting the endocannabinoid system seems essential to differently manage several pathological conditions such as intestinal inflammation, obesity, diabetes and fatty liver disease. However, to date, few drugs have been tested in clinical trials. CB1-antagonists and CB2 agonists appear to be viable therapeutic options that need to be explored for the management of liver diseases. As HCV cure rates are coming close to 100% in the era of direct-acting antivirals, it is especially important to be able to identify modifiable risk factors of complications and death in HIV-HCV coinfected patients, as well as possible levers for intervention. Given the persistence of metabolic risk factors after HCV eradication, cannabis-based therapies need to be evaluated both as preventive and therapeutic tools in patients living with or at risk of liver steatosis, possibly in combination with existing conventional approaches.”

https://www.tandfonline.com/doi/full/10.1080/14787210.2018.1473764