Tag Archives: CB2

Synthesis and biological evaluation of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist.

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“Cannabinoid receptor 2 (CB2) selective agonists and inverse agonists possess significant potential as therapeutic agents for regulating inflammation and immune function.

Although CB2 agonists have received the greatest attention, it is emerging that inverse agonists also manifest anti-inflammatory activity.

In process of designing new cannabinoid ligands we discovered that the 2,6-dihydroxy-biphenyl-aryl methanone scaffold imparts inverse agonist activity at CB2 receptor without functional activity at CB1. To further explore the scaffold we synthesized a series of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone analogs and evaluated the CB1 and CB2 affinity, potency, and efficacy.

The studies reveal that an aromatic C ring is required for inverse agonist activity and that substitution at the 4 position is optimum. The resorcinol moiety is required for optimum CB2 inverse agonist activity and selectivity. Antagonist studies against CP 55,940 demonstrate that the compounds 41 and 45 are noncompetitive antagonists at CB2.”

http://www.ncbi.nlm.nih.gov/pubmed/26275680

Novel Triazolopyrimidine-Derived Cannabinoid Receptor 2 Agonists As Potential Treatment for Inflammatory Kidney Diseases.

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“The cannabinoid receptor 2 (CB2) system is described to modulate various pathological conditions, including inflammation and fibrosis.

A series of new heterocyclic small-molecule CB2 receptor agonists were identified from a high-throughput screen…

A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound 39 was also protective in a model of renal fibrosis.

Oral treatment with 39 at 3 mg kg-1 per day significantly decreased the amount of fibrosis by ∼40 % which was induced by unilateral ureter obstruction.”

http://www.ncbi.nlm.nih.gov/pubmed/26228928

Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist.

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“Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease.

Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury.

We have previously reported the receptor affinity of 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury.

Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940.

The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined.

Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.”

http://www.ncbi.nlm.nih.gov/pubmed/26196013

Bone cell-autonomous contribution of type 2 cannabinoid receptor to breast cancer induced osteolysis.

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“The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumour growth, bone remodelling and bone pain.

However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here, we found that the CB2 selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micro-molar concentrations…

When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands, depending upon cell type and concentration used.

We therefore conclude that both, CB2 selective activation and antagonism have potential efficacy in cancer associated bone disease but further studies are warranted and ongoing.”

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis.

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“Alpha/beta-hydrolase domain 6 (ABHD6) is a novel 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, that can fine-tune the endocannabinoid signaling in the central nervous system.

Recently we and others have demonstrated the protective effect of ABHD6 inhibition in the animal models of traumatic brain injury and epileptic seizures. In this study, we investigated the role of targeting ABHD6 in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS)…

These results suggest that inhibition of ABHD6 might be used as an ideal strategy for the treatment of MS and other neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26189763

Time-Dependent Protection of CB2 Receptor Agonist in Stroke.

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“Recent studies have indicated that type 2 cannabinoid receptor (CB2R) agonists reduce neurodegeneration after brain injury through anti-inflammatory activity.

The purpose of this study was to examine the time-dependent interaction of CB2R and inflammation in stroke brain.

In conclusion, our data support a time-dependent neuroprotection of CB2 agonist in an animal model of stroke.

Delayed post- treatment with PPAR-γ agonist induced behavioral recovery and microglial suppression; early treatment with CB2R agonist suppressed neurodegeneration in stroke animals.”

http://www.ncbi.nlm.nih.gov/pubmed/26186541

http://www.thctotalhealthcare.com/category/stroke-2/

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts.

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“The bone remodeling process is influenced by various factors, including estrogens and transmitters of the endocannabinoid system. In osteoblasts, cannabinoid receptors 2 (CB-2) are expressed at a much higher level compared to CB-1 receptors. Previous studies have shown that estrogens could influence CB-2 receptor expression.

In the present study, the possible interactions of a specific CB-2 agonist and a specific CB-2 antagonist/inverse agonist with 17-β-estradiol were investigated in primary human osteoblasts (HOB)…

In conclusion, for the first time a synergistic interaction between 17-β-estradiol and specific CB-2 antagonist/inverse agonist was observed in HOB.

Understanding the molecular pathways of this interaction would be of great importance in developing more efficient and safer drugs for treating or preventing bone diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26171165

CB2 receptor agonists protect human dopaminergic neurons against damage from HIV-1 gp120.

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“The global pandemic of HIV infection currently afflicts 34 million individuals, has killed over 25 million people since 1981, and is the cause of death in an estimated 1.8 million people per year.

Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND) remains a serious threat to AIDS patients…

Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes.

Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model…

These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from gp120 in a variety of ways, acting principally through the CB2 receptors and microglia.

Overall, this study confirms that gp120 is capable of damaging human dopaminergic neurons, that this damage involves human microglia, and that synthetic cannabinoids can alleviate this damage through mechanisms involving human microglia.

Thus, the results of these experiments set the stage for further studies designed to tease out the role human microglia have in the mechanisms underlying the toxic effects of HIV-1 on human dopaminergic neurons and understanding the microglial-centered mechanisms underlying the protective effects of selected synthetic cannabinoids.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798286/

Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced β-Endorphin Release.

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“Activation of cannabinoid receptor-2 (CB2) results in β-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception.

Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/26108183

CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion.

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“Preventive treatment with cannabinoid agonists has been reported to reduce the infarct size in a mouse model of myocardial ischemia/reperfusion.

Here we investigated the possible cardioprotective effect of selective CB(2) cannabinoid receptor activation during ischemia.

Our data suggest that administration during ischemia reduces the infarct size in a mouse model of myocardial ischemia/reperfusion through a direct cardioprotective activity on cardiomyocytes and neutrophils.”

http://www.ncbi.nlm.nih.gov/pubmed/19162037