“Cannabinoid receptor 2 (CB2), a G protein-coupled receptor (GPCR), is a promising target for the treatment of neuropathic pain, osteoporosis, immune system, cancer, and drug abuse.”
“The CB2 cannabinoid receptor remains a tantalizing, but unrealized therapeutic target. CB2 receptor ligands belong to varied structural classes and display extreme functional selectivity. Here we have screened diverse CB2 receptor ligands at canonical (inhibition of adenylyl cyclase) and non-canonical (arrestin recruitment) pathways. The non-classical cannabinoid, CP55940 was the most potent agonist for both pathways, while the classical cannabinoid ligand JWH133 was the most efficacious agonist amongst all the ligands profiled in cyclase assays. In the cyclase assay, other classical cannabinoids showed little (Δ9THC, KM233) to no efficacy (L759633 and L759656). Most aminoalkylindoles including WIN55212-2 were moderate efficacy agonists. The cannabilactone AM1710 was equi-efficacious to CP55940 to inhibit adenylyl cyclase, albeit with lower potency. In the arrestin recruitment assays, all classical cannabinoid ligands failed to recruit arrestins, indicating a bias towards G protein coupling for this class of compound. All aminoalkylindoles tested, except for WIN55212-2 and UR144, failed to recruit arrestin. WIN55212-2 was a low efficacy agonist for arrestin recruitment, while UR144 was arrestin biased with no significant inhibition of cyclase. Endocannabinoids were G protein biased with no arrestin recruitment. The diarylpyrazole antagonist, SR144528 was an inverse agonist in cyclase and arrestin recruitment assays while the aminoalkylindole AM630 and carboxamide JTE907 were inverse agonists in cyclase but low efficacy agonists in arrestin recruitment assays. Thus CB2 receptor ligands display strong and varied functional selectivity at both pathways. Therefore extreme care must be exercised when using these compounds to infer the role of CB2 receptors in vivo.”
“The function of the CB2 cannabinoid receptor in the brain has long been a matter of debate. In this issue of Neuron, Stempel et al. (2016) describe a mechanism whereby endocannabinoid production leads to a cell-intrinsic hyperpolarization that controls self activity.”
“Breast cancer is the leading cause of cancer-related deaths among women aged 34–50 worldwide, and is the most commonly diagnosed metastasizing tumor in women of all ages. Despite advances in understanding breast cancer as a disease, there remains a critical need for novel disease-modifying therapeutics.
Nonspecific cannabinoids, cannabinoid receptor 2 (CB2)-selective, as well as cannabinoid receptor 1 (CB1)-selective compounds have yielded similar antitumor results in several tumor models. The lack of neuronal expression of CB2 receptors precludes CB2 selective compounds from inducing the psychotropic effects that typically accompany CB1 activation.
Our group and others have shown that CB2 agonists displaying selectivity for the CB2 receptor can decrease tumor cell viability and significantly attenuate cancer-induced bone pain without displaying psychoactive or addictive properties.
…antitumor effects of cannabinoids have been demonstrated in a variety of tumor models…
The antiproliferative effects of a CB2 agonist along with our previous work demonstrating significant efficacy in inhibiting bone cancer pain and slowing bone loss in a murine model of advanced breast cancer strongly suggest that CB2 agonists should be investigated in humans as adjunct therapy for advanced stages of breast cancer.
“Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder.
The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells.
The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children.
In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls.
This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.
This study demonstrates a biomolecular effect of GcMAF in BMDMs from autistic patients, providing further evidence for a positive use of this molecule in autism treatment. It also seems likely that the CB2R is a potential therapeutic target for Autism and autism spectrum disorders (ASDs) interventions.”
“Cannabinoid compounds, both nonspecific as well as agonists selective for either cannabinoid receptor 1 (CB1) or cannabinoid receptor 2 (CB2), have been shown to modulate the tumor microenvironment by inducing apoptosis in tumor cells in several model systems.
The mechanism of this modulation remains only partially delineated, and activity induced via the CB1 and CB2 receptors may be distinct despite significant sequence homology and structural similarity of ligands.
The results of this work characterize the actions of a CB2-selective agonist on breast cancer cells in a syngeneic murine model representing how a clinical presentation of cancer progression and metastasis may be significantly modulated by a G-protein-coupled receptor.”
“In the brain, there is a delicate interplay of signaling substances and cellular activity. Scientists have now identified another key player within this ensemble. In a laboratory study they found that the ‘cannabinoid type 2 receptor’ influences information processing inside the hippocampus. The research results might help advance our understanding of schizophrenia and Alzheimer’s, say the authors.” https://www.sciencedaily.com/releases/2016/05/160502111228.htm
“The cannabinoid type 2 receptor – also called “CB2 receptor” – is a special membrane protein. Its function is to receive chemical signals that control cellular activity. “Until now, this receptor was considered part of the immune system without function in nerve cells. However, our study shows that it also plays an important role in the signal processing of the brain,” explains Professor Dietmar Schmitz, Speaker for the DZNE-Site Berlin and Director of the Neuroscience Research Center of the Charité (NWFZ/NeuroCure).” https://scienceblog.com/483935/neuroscientists-discover-previously-unknown-function-cannabinoid-receptor/
“Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs).
The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB1Rs.
We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB1Rs.
The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB2Rs, as shown by a combined pharmacogenetic and immunohistochemical approach.
Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron.
CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo.
To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.”
“The endocannabinoid system (ECS) includes endocannabinoids (eCBs), cannabinoid (CB) receptors and the enzymes that are responsible for endocannabinoid production and metabolism. The ECS has been reported to be present in both brain and peripheral tissues.
Recent studies have indicated that eCBs and their receptors are involved in the development of various liver diseases. They were found to be altered in response to many danger factors.
It is generally accepted that eCB may exert a protective action via CB2 receptors in different liver diseases. However, eCBs have also been demonstrated to have pathogenic role via their CB1 receptors.
Although the therapeutic potential of CB1 receptor blockade in liver diseases is limited by its neuropsychiatric side effects, many studies have been conducted to search for novel, peripherally restricted CB1 antagonists or CB2 agonists, which may minimize their neuropsychiatric side effects in clinical use.
This review summarizes the current understanding of the ECS in liver diseases and provides evidence for the potential to develop new therapeutic strategies for the treatment of these liver diseases.”
“Targeting type-2 cannabinoid receptor (CB2) is considered a feasible strategy to develop new drugs for the treatment of diseases like neuropathic pain, chronic inflammation, neurodegenerative disorders and cancer.
Such drugs are devoid of the undesired central side effects that are typically mediated by the CB1 receptor.
In this work we synthesized 18 biphenylic carboxamides as new CB2-selective ligands and evaluated their pharmacological profiles. The functional activity of these compounds is strongly influenced by the nature of the substituent at position 4′ and 5 of the biphenyl scaffold.
Position 5 seems to be responsible for the agonist or inverse agonist behaviour independently of the substituent in position 4′, with the exception of the methoxyl group which transforms both full agonists and inverse agonists into neutral antagonists.
This study provides a novel complete toolbox of CB2 functional modulators that derive from the same chemical scaffold. Such probes may be useful to investigate the biological role of CB2 receptors in cellular assays.”