Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain.

Posted on February 19, 2016 by David

“We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity.

Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol, and behaves as cannabinoid (CB1/CB2) receptor indirect agonist.

Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin.

Given these evidences, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/26888301

Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.

Posted on February 19, 2016 by David

“Nicotine, the main psychoactive component of tobacco, and (-)-Δ⁹-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior.

Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC…

Recently-developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence.

These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/26888056

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen-induced pulmonary inflammation in mice.

Posted on February 8, 2016 by David

“Accumulation of activated eosinophils in tissue is a hallmark of allergic inflammation.

The endocannabinoid 2-arachidonoylglycerol (2-AG) has been proposed to elicit eosinophil migration in a CB₂ receptor/G_i/o -dependent manner.

Here we explored the direct contribution of specific CB₂ receptor activation to human and mouse eosinophil effector function in vitro and in vivo.

Our data indicate that CB₂ may directly contribute to the pathogenesis of eosinophil-driven diseases. Moreover, we provide new insights into the molecular mechanisms underlying the CB₂ -mediated priming of eosinophils. Hence, antagonism of CB₂ receptors may represent a novel pharmacological approach for the treatment of allergic inflammation and other eosinophilic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26850094

Prevention of drug priming- and cue-induced reinstatement of MDMA-seeking behaviors by the CB1 cannabinoid receptor antagonist AM251.

Posted on January 23, 2016 by David

“3,4-Methylenedioxymethamphetamine (MDMA), a methamphetamine (METH) derivative, exhibits METH-like actions at monoamine transporters and positive reinforcing effects in rodents and primates.

The purposes of the present study were to determine whether cross-reinstatement would be observed between MDMA and METH and if the cannabinoid receptor, a receptor known to play critical roles in the brain reward system, could modulate MDMA craving…

These findings show that MDMA has obvious addictive potential for reinstating drug-seeking behavior and that METH can be an effective stimulus for reinstating MDMA-seeking behaviors.

Furthermore, based on the attenuating effect of AM251 in the reinstatement of MDMA-seeking behaviors, drugs that suppress CB1 receptors may be used in treatment of MDMA dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/26796595

http://www.thctotalhealthcare.com/category/addiction/

CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction.

Posted on January 14, 2016 by David

“The endocannabinoid system can modulate energy homeostasis by regulating feeding behaviour as well as peripheral energy storage and utilization.

Importantly, many of its metabolic actions are mediated through the cannabinoid type 1 receptor (CB1R), whose hyperactivation is associated with obesity and impaired metabolic function.

Herein, we explored the effects of administering rimonabant, a selective CB1R inverse agonist, upon key metabolic parameters in young (4 month old) and aged (17 month old) adult male C57BL/6 mice…

Collectively, our findings indicate a key role for CB1R in aging-related insulin resistance and metabolic dysfunction and highlight CB1R blockade as a potential strategy for combating metabolic disorders associated with aging.”

http://www.ncbi.nlm.nih.gov/pubmed/26757949

Interactions between the endocannabinoid and nicotinic cholinergic systems: preclinical evidence and therapeutic perspectives.

Posted on January 6, 2016 by David

“Many behavioral and neurochemical effects of nicotine that are related to its addictive potential are reduced by pharmacological blockade or genetic deletion of type-1 cannabinoid receptors, inhibition of endocannabinoid uptake or metabolic degradation, and activation of peroxisome proliferator-activated-receptor-α. On the other hand, cholinergic antagonists at α7 nicotinic acetylcholine receptors as well as endogenous negative allosteric modulators of these receptors are effective in blocking dependence-related effects of cannabinoids.

CONCLUSIONS:

Pharmacological manipulation of the endocannabinoid system and endocannabinoid-like neuromodulators shows promise in the treatment of nicotine dependence and in relapse prevention. Likewise, drugs acting at nicotinic acetylcholine receptors might prove useful in the therapy of cannabinoid dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/26728894

Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor.

Posted on December 4, 2015 by David

“Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity.

The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives.

This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions.

We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization.

This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/26633590

Liver’s cannabinoid receptors could be targeted to combat liver cancer in some patients

Posted on December 1, 2015 by David

“A new study reveals that the liver’s cannabinoid receptors could be targeted to fight liver cancer in some patients; and it offers a way to predict what treatments have the best chance of working.

The body’s own marijuana-like substances, — called endocannabinoids — are known to increase the biosynthesis of fatty acids in the liver by activating cannabinoid type 1 receptors (CB1). CB1 receptors can be found in the brain, lungs, liver and kidney, and they are involved in a number of physiological processes, including mood, appetite, pain sensation and memory.

The study found that the expression of these receptors increased in cancerous liver samples, when compared with cancer-free samples. This suggests that drugs that block CB1 receptors may be effective against HCC.

“Although such drugs were found to cause unwanted psychiatric side effects, non brain-penetrant CB1 receptor antagonists devoid of such side effects — but retaining therapeutic efficacy via peripheral CB1 receptors — are currently being developed,” says study co-author George Kunos, scientific director at the U.S. National Institute on Alcohol Abuse and Alcoholism (NIAAA).”

http://www.news-medical.net/news/20151123/Livers-cannabinoid-receptors-could-be-targeted-to-combat-liver-cancer-in-some-patients.aspx

Involvement of opioid system in antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251 after physical stress in mice.

Posted on November 28, 2015 by David

“Cannabinoid inverse agonists possess antidepressant-like properties…

Numerous studies reported the interaction between opioid and cannabinoid pathways.

In this study, we used acute foot-shock stress in mice to investigate the involvement of opioid pathway in the antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251.

In conclusion, the present study for the first time revealed the possible role of opioid signaling in the antidepressant-like properties of AM-251 in foot-shock stress model. “

http://www.ncbi.nlm.nih.gov/pubmed/26609670

The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Δ9-tetrahydrocannabinol acting through CB1 receptors.

Posted on November 23, 2015 by David

“Sativex®, an equimolecular combination of Δ9-tetrahydrocannabinol-botanical drug substance (Δ9-THC-BDS) and cannabidiol-botanical drug substance (CBD-BDS), is a licensed medicine that may be prescribed for alleviating specific symptoms of multiple sclerosis (MS) such as spasticity and pain.

However, further evidence suggest that it could be also active as disease-modifying therapy given the immunomodulatory, anti-inflammatory and cytoprotective properties of their two major components.

In this study, we investigated this potential in the experimental autoimmune encephalitis (EAE) model of MS in mice.

We compared the effect of a Sativex-like combination of Δ9-THC-BDS (10mg/kg) and CBD-BDS (10mg/kg) with Δ9-THC-BDS (20mg/kg) or CBD-BDS (20mg/kg) administered separately by intraperitoneal administration to EAE mice.

Treatments were initiated at the time that symptoms appear and continued up to the first relapse of the disease.

The results show that the treatment with a Sativex-like combination significantly improved the neurological deficits typical of EAE mice, in parallel with a reduction in the number and extent of cell aggregates present in the spinal cord which derived from cell infiltration to the CNS.

These effects were completely reproduced by the treatment with Δ9-THC-BDS alone, but not by CBD-BDS alone which only delayed the onset of the disease without improving disease progression and reducing the cell infiltrates in the spinal cord.

Next, we investigated the potential targets involved in the effects of Δ9-THC-BDS by selectively blocking CB1 or PPAR-γ receptors, and we found a complete reversion of neurological benefits and the reduction in cell aggregates only with rimonabant, a selective CB1 receptor antagonist.

Collectively, our data support the therapeutic potential of Sativex as a phytocannabinoid formulation capable of attenuating EAE progression, and that the active compound was Δ9-THC-BDS acting through CB1 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/26590655