“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.”
Tag Archives: cannabinoid receptors
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.”
Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis.
“The endocannabinoid system (ECS) exerts key roles in the development of liver fibrosis and fatty liver, two diseases that promote the development of hepatocellular carcinoma (HCC).
Although cannabinoids exert potent antitumour effects in vitro, the contribution of the ECS to carcinogenesis in vivo remains elusive.
CONCLUSIONS:
Similar to their role in fibrogenesis, CB1 and CB2 exert opposite effects on hepatocarcinogenesis and may provide novel therapeutic targets.”
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…”
Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.
“Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ9-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse.
These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability.”
Neuroprotection by Cannabinoids in Huntington’s Disease
“A Double Blind, Randomized, Cross Over, Placebo Controlled Phase 2 Clinical Trial to Asses Neuroprotection by Cannabinoids in Huntington’s Disease.”
“Huntington’s disease (HD) is a progressive neurodegenerative disorder, related to an abnormal expansion of CAG triplets in the huntingtin gene, characterized by motor, cognitive and behavioral abnormalities, without known effective symptomatic treatment and without known disease slowing strategy. The most severe neuropathological lesions observed in HD take place in the striatum, one brain area important in motor control and rich in cannabinoid receptors (CBR). CBR are subdivided in two classes: CB1R are located in neurons and play a role in neuronal function; CB2R in brain are located mostly in microglia and modulate neuroinflammation.
CBR disappear early in the course of HD, before there is a massive drop out of cells in the striatum. Cannabinoid transmission is also an early event in brains of animal models of HD. In R6/2 mice, which carry large CAG expansions and develop an early and severe HD phenotype the suppression of the CB1R gene further accelerate the development of a severe clinical syndrome and the characteristic brain inclusions and abnormalities of synaptic density. R6/2 treated mice treated with cannabinoids improve their clinical phenotype, their brain lesions, the synaptic density and the levels of BNDF, a neurotrophic factor which enhances survival and resistance of striatal neurons.
Preliminary studies of cannabinoids in patients with HD have shown that these compounds are safe in these patients.”
Potentiation of cannabinoid-induced cytotoxicity in Mantle Cell Lymphoma through modulation of ceramide metabolism
“Ceramide accumulation is a widely described event in cancers after various treatments.
Ceramide levels are elevated in Mantle Cell Lymphoma (MCL) cells following treatment with cannabinoids.
In previous publications we and others observed that induction of ceramide accumulation by cannabinoids leads to apoptosis in MCL, glioma and pancreatic cancer.
Here, we investigated the pathways of ceramide accumulation in the MCL cell line Rec-1 using the stable endocannabinoid analogue R(+)-methanandamide (R-MA).
Our findings suggest that R-MA induces cell death in MCL via CB1-mediated upregulation of the de novo ceramide synthesis pathway.
This is the first study showing that the cytotoxic effect of a cannabinoid can be enhanced by modulation of ceramide metabolism.
The results suggest that interference with ceramide conversion may provide a tool to enhance the targeted cell death-promoting effects of cannabinoids in MCL and other malignant lymphomas overexpressing the CB1 receptor.
Cannabinoids have been suggested as a new non-toxic therapeutic option for cancer treatment.”
Cannabinoid receptors in mantle cell lymphoma
“Mantle cell lymphoma (MCL) is a non-curable B cell lymphoma that in several independent studies have been shown to express higher levels of CB1 and CB2 than non-malignant B cells.
The endocannabinoid system is dysregulated in many types of cancer and is involved in the regulation of survival and proliferation of cancer cells and cancer stem cells, in cancer metabolism, as well as in pro-metastatic events such as angiogenesis, migration and invasion.
Previous in vitro studies of MCL cell lines and primary ex vivo isolated tumor cells have demonstrated that high concentrations of cannabinoid receptor ligands induced proliferation arrest and programmed cell death.
All together, the data suggest that perturbations in the endocannabinoid system participate in the regulation of multi-functional cell responses regarding proliferation, migration and cell death control.
Therefore, it can be concluded that further studies on pharmacological modulation of endocannabinoid accumulation and/or signaling offers an interesting option for novel anti-lymphoma therapy.”
Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma.
“We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB(1) and CB(2)).
In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated.
The present data suggest that targeting CB(1)/CB(2) may have therapeutic potential for the treatment of mantle cell lymphoma.”