“Displacement binding assays are nonfunctional assays mostly used with the aim of determining whether a certain compound (plant-derived or synthetic) is able to bind to a specific receptor with high affinity. Here, we describe the displacement binding assay that is carried out with a radioligand and CHO (Chinese Hamster Ovarian) cells stably transfected with the human cannabinoid CB2 receptor.”
Tag Archives: CB2
Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts.
“Recently, it has also been demonstrated that the pleiotropic cannabinoid system is involved in both liver and pancreatic fibrosis. Furthermore, cannabinoids may play a pro- or anti-fibrogenic role depending on their interaction with CB1r or CB2r.
This raises the possibility that pharmacologic modulation of the endocannabinoid system could be a target to limit tissue damage in pathologic fibrosis.
It has been demonstrated that the endocannabinoid system is up-regulated in pathologic fibrosis and that modulation of the cannabinoid receptors might limit the progression of uncontrolled fibrogenesis.
Both CB1 and CB2 receptors were over-expressed in dcSSc fibroblasts compared with healthy controls.
Our preliminary findings suggest that cannabinoids are provided with an anti-fibrotic activity, thereby possibly representing a new class of agents targeting fibrosis diseases.”
http://rheumatology.oxfordjournals.org/content/48/9/1050.long
Cannabinoid receptor 2 (CB2) agonists and antagonists: a patent update.
“Modulation of the CB2 receptor is an interesting approach for pain and inflammation, arthritis, addictions, neuroprotection, and cancer, among other possible therapeutic applications, and is devoid of central side effects.
Structural diversity of CB2 modulator scaffolds characterized the patent literature.
Several CB2 agonists reached clinical Phase II for pain management and inflammation.
Other therapeutic applications need to be explored such as neuroprotection and/or neurodegeneration.”
Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer’s disease
“Brain disorders, including Alzheimer’s disease (AD), often involve specific early alterations in the metabolism of glucose in the brain.
The idea of alleviating symptoms of dementia by boosting cerebral energy metabolism has been toyed with for decades, yet safe pharmacological agents with well characterized mechanism of action are still lacking.
In this sense, we have investigated here the local cerebral glucoregulatory potential of the endocannabinoid system in rodents.
Cannabinoid CB2 receptors (CB2Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations.
Together, these results reveal a novel general glucoregulatory role for CB2Rs in the brain, raising therapeutic interest in CB2R agonists as nootropic agents.
In conclusion, the present results provide the first direct pharmacological evidence in vitroand in vivo of a role of CB2R in central glucoregulation.
Additionally, we found that glucoregulation by endogenous CB2R signalling is negatively affected by β-amyloidosis, thought to be the first pathological step in AD.
Therefore, it would be interesting to perform further studies to define how CB2R mediated glucoregulation contributes to the recently discovered therapeutic potential of CB2R agonists in animal models of AD”
http://www.sciencedirect.com/science/article/pii/S0028390816300879
Novel role of cannabinoid receptor 2 in inhibiting EGF/EGFR and IGF-I/IGF-IR pathways in breast cancer.
“Breast cancer is the second leading cause of cancer deaths among women.
Cannabinoid receptor 2 (CNR2 or CB2) is an integral part of the endocannabinoid system.
Although CNR2 is highly expressed in the breast cancer tissues as well as breast cancer cell lines, its functional role in breast tumorigenesis is not well understood.
We observed that estrogen receptor-α negative (ERα-) breast cancer cells highly express epidermal growth factor receptor (EGFR) as well as insulin-like growth factor-I receptor (IGF-IR). We also observed IGF-IR upregulation in ERα+ breast cancer cells.
In addition, we found that higher CNR2 expression correlates with better recurrence free survival in ERα- and ERα+ breast cancer patients.
Our studies showed that CNR2 activation inhibited EGF and IGF-I-induced migration and invasion of ERα+ and ERα- breast cancer cells.
In conclusion, we show that CNR2 activation suppresses breast cancer through novel mechanisms by inhibiting EGF/EGFR and IGF-I/IGF-IR signaling axes.”
Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis
“Some of cannabinoids, which are chemical compounds contained in marijuana, are immunosuppressive.
One of the receptors, CB receptor 1 (CB1), is expressed predominantly by the cells in the central nervous system, whereas CB receptor 2 (CB2) is expressed primarily by immune cells.
Theoretically, selective CB2 agonists should be devoid of psychoactive effects.
In this study, we investigated therapeutic effects of a selective CB2 agonist on arthritis.
The present study suggests that a selective CB2 agonist could be a new therapy for RA that inhibits production of inflammatory mediators from FLS, and osteoclastogenesis.
This is the first report of therapeutic effect of a selective CB2 agonist on CIA.
Although the effect was mild, optimization of dosage and/or treatment protocol might enhance the effect.
Perhaps, more potent selective CB2agonists might solve this problem.
Cannabinoids are pharmacologically active components of Cannabis sativa.”
Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery.
“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.”
Functional selectivity of CB2 cannabinoid receptor ligands at a canonical and non-canonical pathway.
“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.”
A Central Move for CB2 Receptors.
“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.”
Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent
“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.
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 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.
Several groups have shown that both nonselective cannabinoid and CB2-specific compounds decrease breast cancer viability in vitro and in vivo: Δ9-tetrahydrocannabinol and CB2-selective agonist, JWH-133, have been demonstrated to exert considerable antitumoral effects…”