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

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

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Role of the endocannabinoid system in drug addiction.

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

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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

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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

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Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.

Kidney International Home

“The cannabinoid receptor type 2 (CB2) is a G protein-coupled seven transmembrane receptor that transmits endogenous cannabinoid signaling. The role of CB2 in the pathogenesis of kidney injury and fibrosis remains poorly understood.

Here we demonstrate that CB2 was induced, predominantly in kidney tubular epithelium, in various models of kidney disease induced by unilateral ureteral obstruction, adriamycin or ischemia/reperfusion injury.

By using in silico screening and medicinal chemistry modifications, we discovered a novel compound, XL-001, that bound to CB2 with high affinity and selectivity and acted as an inverse agonist. Delayed administration of XL-001 was also effective in ameliorating kidney fibrosis and inflammation.

Thus, CB2 is a pathogenic mediator in kidney fibrosis and targeted inhibition with the novel inverse agonist XL-001 may provide a strategy in the fight against fibrotic kidney diseases.”

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Chronic treatment with the phytocannabinoid Cannabidivarin (CBDV) rescues behavioural alterations and brain atrophy in a mouse model of Rett syndrome.

Neuropharmacology

“Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in the MECP2 gene in about 95% of cases and to date no cure is available.

The endocannabinoid system modulates several physiological processes and behavioural responses that are impaired in RTT and its deregulation has been associated with neuropsychiatric disorders which have symptoms in common with RTT.

The present study evaluated the potential therapeutic efficacy for RTT of cannabidivarin (CBDV), a non-psychotropic phytocannabinoid from Cannabis sativa that presents antagonistic properties on the G protein-coupled receptor 55 (GPR55), the most recently identified cannabinoid receptor.

Present results demonstrate that systemic treatment with CBDV (2, 20, 100 mg/Kg ip for 14 days) rescues behavioural and brain alterations in MeCP2-308 male mice, a validated RTT model. The CBDV treatment restored the compromised general health status, the sociability and the brain weight in RTT mice. A partial restoration of motor coordination was also observed. Moreover, increased levels of GPR55 were found in RTT mouse hippocampus, suggesting this G protein-coupled receptor as new potential target for the treatment of this disorder.

Present findings highlight for the first time for RTT the translational relevance of CBDV, an innovative therapeutic agent that is under active investigation in the clinical setting.”

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Cannabinoids, the Heart of the Matter

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“Cardiovascular disease (CVD) is a global epidemic representing the leading cause of death in some Western countries. Endocannabinoids and cannabinoid‐related compounds may be a promising approach as therapeutic agents for cardiovascular diseases. This review highlights the potential of cannabinoids and their receptors as targets for intervention.

In summary, the endocannabinoid system is highly active in cardiovascular disease states. Modulation of the ECS, CB1, and TRPV1 antagonism, as well as CB2 agonism, have proven to modulate disease state and severity in CVD. Studies are underway to develop drugs to change the course of cardiovascular diseases.

If therapeutic potential resides in a single molecule component or a derivative, then production and regulation of the therapy are straightforward. If the efficacious agent is a complex mixture that reflects some or all of the secondary metabolome complexity of Cannabis sativa, then safe and consistent production become challenging.”  http://jaha.ahajournals.org/content/7/14/e009099https://www.ncbi.nlm.nih.gov/pubmed/30006489

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Assessment of Cannabinoids Agonist and Antagonist in Invasion Potential of K562 Cancer Cells

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“The prominent hallmark of malignancies is the metastatic spread of cancer cells. Recent studies have reported that the nature of invasive cells could be changed after this phenomenon, causing chemotherapy resistance.

It has been demonstrated that the up-regulated expression of matrix metalloproteinase (MMP) 2/MMP-9, as a metastasis biomarker, can fortify the metastatic potential of leukemia.

Furthermore, investigations have confirmed the inhibitory effect of cannabinoid and endocannabinoid on the proliferation of cancer cells in vitro and in vivo.

Our findings clarifies that CB1 receptors are responsible for anti-invasive effects in the K562 cell line.”

https://www.ncbi.nlm.nih.gov/pubmed/29883990

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Endocannabinoids in Body Weight Control.

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“Maintenance of body weight is fundamental to maintain one’s health and to promote longevity. Nevertheless, it appears that the global obesity epidemic is still constantly increasing.

Endocannabinoids (eCBs) are lipid messengers that are involved in overall body weight control by interfering with manifold central and peripheral regulatory circuits that orchestrate energy homeostasis.

Initially, blocking of eCB signaling by first generation cannabinoid type 1 receptor (CB1) inverse agonists such as rimonabant revealed body weight-reducing effects in laboratory animals and men. Unfortunately, rimonabant also induced severe psychiatric side effects.

At this point, it became clear that future cannabinoid research has to decipher more precisely the underlying central and peripheral mechanisms behind eCB-driven control of feeding behavior and whole body energy metabolism.

Here, we will summarize the most recent advances in understanding how central eCBs interfere with circuits in the brain that control food intake and energy expenditure. Next, we will focus on how peripheral eCBs affect food digestion, nutrient transformation and energy expenditure by interfering with signaling cascades in the gastrointestinal tract, liver, pancreas, fat depots and endocrine glands.

To finally outline the safe future potential of cannabinoids as medicines, our overall goal is to address the molecular, cellular and pharmacological logic behind central and peripheral eCB-mediated body weight control, and to figure out how these precise mechanistic insights are currently transferred into the development of next generation cannabinoid medicines displaying clearly improved safety profiles, such as significantly reduced side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/29849009

http://www.mdpi.com/1424-8247/11/2/55

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Mechanistic Potential and Therapeutic Implications of Cannabinoids in Nonalcoholic Fatty Liver Disease.

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“Nonalcoholic fatty liver disease (NAFLD) is comprised of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). It is defined by histologic or radiographic evidence of steatosis in the absence of alternative etiologies, including significant alcohol consumption, steatogenic medication use, or hereditary disorders.

NAFLD is now the most common liver disease, and when NASH is present it can progress to fibrosis and hepatocellular carcinoma. Different mechanisms have been identified as contributors to the physiology of NAFLD; insulin resistance and related metabolic derangements have been the hallmark of physiology associated with NAFLD.

The mainstay of treatment has classically involved lifestyle modifications focused on the reduction of insulin resistance. However, emerging evidence suggests that the endocannabinoid system and its associated cannabinoid receptors and ligands have mechanistic and therapeutic implications in metabolic derangements and specifically in NAFLD.

Cannabinoid receptor 1 antagonism has demonstrated promising effects with increased resistance to hepatic steatosis, reversal of hepatic steatosis, and improvements in glycemic control, insulin resistance, and dyslipidemia. Literature regarding the role of cannabinoid receptor 2 in NAFLD is controversial.

Exocannabinoids and endocannabinoids have demonstrated some therapeutic impact on metabolic derangements associated with NAFLD, although literature regarding direct therapeutic use in NAFLD is limited. Nonetheless, the properties of the endocannabinoid system, its receptors, substrates, and ligands remain a significant arena warranting further research, with potential for a pharmacologic intervention for a disease with an anticipated increase in economic and clinical burden.”

https://www.ncbi.nlm.nih.gov/pubmed/29843404

http://www.mdpi.com/2305-6320/5/2/47

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