Tag Archives: antagonists

The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism–or inverse agonism–as potential obesity treatment and other therapeutic use.

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Abstract

“There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Towards this end, antagonists of cannabinoid receptors have been designed through rational drug discovery efforts. Devoid of the abuse concerns that confound and impede the use of cannabinoid receptor agonists for legitimate medical purposes, investigation of the use of cannabinoid receptor antagonists as possible pharmacotherapeutic agents is currently being actively investigated. The compound furthest along this pathway is rimonabant, a selective CB(1) (cannabinoid receptor subtype 1) antagonist, or inverse agonist, approved in the European Union and under regulatory review in the United States for the treatment of obesity. This article summarizes the basic science of the endocannabinoid system and the therapeutic potential of cannabinoid receptor antagonists, with emphasis on the treatment of obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/17489873

Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis.

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Abstract

“The endogenous cannabinoid (CB) (endocannabinoid) signaling system is involved in a variety of (patho)physiological processes, primarily by virtue of natural, arachidonic acid-derived lipids (endocannabinoids) that activate G protein-coupled CB1 and CB2 receptors. A hyperactive endocannabinoid system appears to contribute to the etiology of several disease states that constitute significant global threats to human health. Consequently, mounting interest surrounds the design and profiling of receptor-targeted CB antagonists as pharmacotherapeutics that attenuate endocannabinoid transmission for salutary gain. Experimental and clinical evidence supports the therapeutic potential of CB1 receptor antagonists to treat overweight/obesity, obesity-related cardiometabolic disorders, and substance abuse. Laboratory data suggest that CB2 receptor antagonists might be effective immunomodulatory and, perhaps, anti-inflammatory drugs. One CB1 receptor antagonist/inverse agonist, rimonabant, has emerged as the first-in-class drug approved outside the United States for weight control. Select follow-on agents (taranabant, otenabant, surinabant, rosonabant, SLV-319, AVE1625, V24343) have also been studied in the clinic. However, rimonabant’s market withdrawal in the European Union and suspension of rimonabant’s, taranabant’s, and otenabant’s ongoing development programs have highlighted some adverse clinical side effects (especially nausea and psychiatric disturbances) of CB1 receptor antagonists/inverse agonists. Novel CB1 receptor ligands that are peripherally directed and/or exhibit neutral antagonism (the latter not affecting constitutive CB1 receptor signaling) may optimize the benefits of CB1 receptor antagonists while minimizing any risk. Indeed, CB1 receptor-neutral antagonists appear from preclinical data to offer efficacy comparable to or better than that of prototype CB1 receptor antagonists/inverse agonists, with less propensity to induce nausea. Continued pharmacological profiling, as the prelude to first-in-man testing of CB1 receptor antagonists with unique modes of targeting/pharmacological action, represents an exciting translational frontier in the critical path to CB receptor blockers as medicines.”

http://www.ncbi.nlm.nih.gov/pubmed/19249987

Inverse agonism and neutral antagonism at cannabinoid CB1 receptors.

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Abstract

“There are at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release whereas CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous cannabinoid receptor agonists also exist and these “endocannabinoids” together with their receptors constitute the “endocannabinoid system”. These discoveries were followed by the development of a number of CB1- and CB2-selective antagonists that in some CB1 or CB2 receptor-containing systems also produce “inverse cannabimimetic effects”, effects opposite in direction from those produced by cannabinoid receptor agonists. This review focuses on the CB1-selective antagonists, SR141716A, AM251, AM281 and LY320135, and discusses possible mechanisms by which these ligands produce their inverse effects: (1) competitive surmountable antagonism at CB1 receptors of endogenously released endocannabinoids, (2) inverse agonism resulting from negative, possibly allosteric, modulation of the constitutive activity of CB1 receptors in which CB1 receptors are shifted from a constitutively active “on” state to one or more constitutively inactive “off” states and (3) CB1 receptor-independent mechanisms, for example antagonism of endogenously released adenosine at A1 receptors. Recently developed neutral competitive CB1 receptor antagonists, which are expected to produce inverse effects through antagonism of endogenously released endocannabinoids but not by modulating CB1 receptor constitutive activity, are also discussed. So too are possible clinical consequences of the production of inverse cannabimimetic effects, there being convincing evidence that released endocannabinoids can have “autoprotective” roles.”

http://www.ncbi.nlm.nih.gov/pubmed/15670612

Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity.

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Abstract

“Obesity is a global problem with often strong neurobiological underpinnings. The cannabinoid 1 receptor (CB1R) was put forward as a promising drug target for antiobesity medication. However, the first marketed CB1R antagonist/inverse agonist rimonabant was discontinued, as its use was occasionally associated with negative affect and suicidality. In artificial cell systems, CB1Rs can become constitutively active in the absence of ligands. Here, we show that such constitutive CB1R activity also regulates GABAergic and glutamatergic neurotransmission in the ventral tegmental area and basolateral amygdala, regions which regulate motivation and emotions. We show that CB1R inverse agonists like rimonabant suppress the constitutive CB1R activity in such regions, and cause anxiety and reduced motivation for reward. The neutral CB1R antagonist NESS0327 does not suppress constitutive activity and lacks these negative effects. Importantly, however, both rimonabant and NESS0327 equally reduce weight gain and food intake. Together, these findings suggest that neutral CB1R antagonists can treat obesity efficiently and more safely than inverse agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/23070073

Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists.

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Abstract

“INTRODUCTION:

Addiction to chemical substances with abuse potential presents medical needs largely unsolved by extant therapeutic strategies. Signal transmission through the cannabinoid-1 receptor (CB1R) in the central nervous system (CNS) modulates neurotransmitters/neuronal pathways contributing to the rewarding properties and hedonic effects of certain nondrug stimuli (e.g., food) and many prototypical addictive drugs, promoting excessive intake and its pathological consequences. Typical CB1R antagonists/inverse agonists reduce the rewarding effects and normalize behavioral phenotypes associated with food and abused drugs, but carry an unacceptable adverse-event profile that may reflect, at least partly, their intrinsic ability to alter basal homeostatic CB1R signaling in the CNS and elicit a negative efficacy response. Alternatively, peripherally biased CB1R inverse agonists with limited CNS permeability and putative CB1R neutral antagonists expressing modest (if any) inverse-agonist efficacy are garnering attention for treating obesity and related cardiometabolic complications with a potentially enhanced benefit-to-risk profile.

AREAS COVERED:

This mini-review calls attention to the proposition that CB1R neutral antagonists offer attractive opportunities for pharmacotherapeutic exploitation in the substance abuse/drug addiction space, whereas the restricted CNS accessibility of peripherally biased CB1R inverse agonists circumscribes their therapeutic utility for this indication.

EXPERT OPINION:

The unique preclinical pharmacology, efficacy profiles, and reduced adverse-event risk of CB1R neutral antagonists make them worthy of translational study for their potential therapeutic application beyond obesity/cardiometabolic disease to include substance-abuse/drug-addiction disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/22335400

Cannabis drug could help fight obesity

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“Apparently scientists have discovered that a natural component of cannabis suppresses the appetite and that discovery may lead to a new class of drugs for treating obesity.

Scientist professor Roger Pertwee, a neuropharmacologist at Aberdeen University, says it was already well known that cannabis stimulated the appetite, but not widely known that the plant also contained substances that produced the opposite effect.

That substance is apparently called THCV and is chemically similar to another cannabis chemical, or cannabinoid, called THC that stimulates the appetite.

As drugs based on THC are already being used to increase the appetite of AIDS patients, the focus is now on developing THCV for use as an anti-obesity drug, said Professor Pertwee.

Pertwee says that cannabis is rich in substances that can mimic the natural or endogenous cannabinoids in the brain, that act as chemical messengers in the nervous pathways, involved in such activities as appetite control or pain relief.

These endogenous cannabinoids seem to act on the reward pathways to the brain, to increase the reward you get when you take food, but can have harmful effects.

By increasing appetite they can increase fat, which can give rise to obesity or overweight.

Drugs are apparently now being developed that can increase the levels of these chemicals in our brains by slowing down the rate at which they disappear once they have been released,says Pertwee.

Professor Pertwee has also found a method of potentially boosting the signals in the brain that are generated by these endogenous cannabinoids.”

http://www.news-medical.net/news/2005/09/10/13067.aspx

Marijuana May Deflect Obesity

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“Cannabis seems to have many different allures. It can produce a “high.” It can give the feeling of munchies. Now, it can possibly help combat obesity. Scientists recently revealed that they found two compounds from cannabis leaves that could up the total energy that the body burns.

Previous studies of two specific compounds demonstrated that they could be used to treat type-two diabetes. The compounds were also discovered to have the ability to reduce cholesterol levels in the blood stream and decrease fat in important organs such as the liver. With the aim of treating patients who have “metabolic syndrome,” the researchers are currently conducting clinical trials in 200 patients with the drug. With “metabolic syndrome,” diabetes, high blood pressure, and obesity combine to heighten the risk of heart disease and stroke in patients.

“We are conducting four Phase 2a clinical trials and we expect some results later this year,” commented Dr. Steph Wright, director of research and development at GW Pharmaceuticals, in a Telegraph article. “The results in animal models have been very encouraging. We are interested in how these drugs effect the fat distribution and utilization in the body as a treatment for metabolic diseases… Humans have been using these plants for thousands of years so we have quite a lot of experience of the chemicals in the plants.”

GW Pharmaceuticals was given a license to grow cannabis in greenhouses that were specially constructed for project. The company produces cannabis plants that have a number of cannabinoids, which are varied compounds of cannabis. They are already working on creating drugs that can assist in treating epilepsy and multiple sclerosis. Interesting enough, when the scientists studied two specific compounds, THCV and cannabioidol, they found that they had the ability to suppress appetite but the effect lasted for a short amount of time. Upon further examination, the investigators discovered that the compounds could influence the fat level in the body as well as its effects to the hormone insulin.

Likewise, the studies of the compounds in mice showed that they increased the metabolism of the animals, causing decreased levels of fat in livers and minimized levels of cholesterol in the blood stream. In particular, THCV showed the ability of boosting the animals’ sensitivity to insulin but also shielding the insulin-producing cells. With these actions, the cells were able to work at a longer and more durable pace.

The researchers hope that the findings will help in the development of treatments for obesity-related illnesses and type-two diabetes.”

http://www.redorbit.com/news/health/1112653330/research-finds-marijuana-may-deflect-obesity/
redOrbit (http://s.tt/1hqLQ)

The role of the endocannabinoid system in skeletal muscle and metabolic adaptations to exercise: potential implications for the treatment of obesity.

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Abstract

“The results of recent studies add the endocannabinoid system, and more specifically CB1 receptor signalling, to the complex mechanisms that negatively modulate insulin sensitivity and substrate oxidation in skeletal muscle. CB1 receptors might become overactive in the skeletal muscle during obesity due to increased levels of endocannabinoids. However, quite surprisingly, one of the most studied endocannabinoids, anandamide, when administered in a sufficient dose, was shown to improve muscle glucose uptake and activate some key molecules of insulin signalling and mitochondrial biogenesis. This is probably because anandamide is only a partial agonist at CB1 receptors and interacts with other receptors (PPARγ, TRPV1), which may trigger positive metabolic effects. This putative beneficial role of anandamide is worth considering because increased plasma anandamide levels were recently reported after intense exercise. Whether the endocannabinoid system is involved in the positive exercise effects on mitochondrial biogenesis and glucose fatty acid oxidation remains to be confirmed. Noteworthy, when exercise becomes chronic, a decrease in CB1 receptor expression in obese metabolically deregulated tissues occurs. It is then tempting to hypothesize that physical activity would represent a complementary alternative approach for the clinical management of endocannabinoid system deregulation in obesity, without the side effects occurring with CB1 receptor antagonists.”

http://www.ncbi.nlm.nih.gov/pubmed/22943701

The endocannabinoid system as a target for obesity treatment.

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Abstract

“Overweight and obesity are major factors contributing to the development of type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). In addition to the many physical and metabolic consequences of obesity, there are also mental health consequences, in particular, the risk for depression. Depression can lead to poor self-care, poor treatment compliance, and possible increased morbidity and mortality from such illnesses as type 2 DM and CVD. Lifestyle modification for the treatment of overweight and obesity is rarely successful over the long term, and use of surgery is limited by eligibility criteria; therefore, researchers and clinicians continue to explore pharmacotherapy, with intense efforts being directed toward the development of agents that, optimally, will reduce weight and simultaneously reduce or eliminate modifiable cardiovascular and metabolic risk factors. Among the promising new agents are the CB(1) receptor antagonists. These agents target receptors of the endocannabinoid system, a neuromodulatory system recently found to influence energy balance, eating behavior, and metabolic homeostasis via central and peripheral mechanisms. In animal and clinical studies, antagonism of CB(1) receptors has resulted in meaningful weight loss and improvement of lipid and glycemic profiles. Thus, these agents may provide a rational and effective approach for the management of not only overweight and obesity but also their metabolic and cardiovascular sequelae.”

http://www.ncbi.nlm.nih.gov/pubmed/19046740

 

The endocannabinoid system: physiology and pharmacology.

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Abstract

“The endogenous cannabinoid system is an ubiquitous lipid signalling system that appeared early in evolution and which has important regulatory functions throughout the body in all vertebrates. The main endocannabinoids (endogenous cannabis-like substances) are small molecules derived from arachidonic acid, anandamide (arachidonoylethanolamide) and 2-arachidonoylglycerol. They bind to a family of G-protein-coupled receptors, of which the cannabinoid CB(1) receptor is densely distributed in areas of the brain related to motor control, cognition, emotional responses, motivated behaviour and homeostasis. Outside the brain, the endocannabinoid system is one of the crucial modulators of the autonomic nervous system, the immune system and microcirculation. Endocannabinoids are released upon demand from lipid precursors in a receptor-dependent manner and serve as retrograde signalling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters, including dopamine. Endocannabinoids are transported into cells by a specific uptake system and degraded by two well-characterized enzymes, the fatty acid amide hydrolase and the monoacylglycerol lipase. Recent pharmacological advances have led to the synthesis of cannabinoid receptor agonists and antagonists, anandamide uptake blockers and potent, selective inhibitors of endocannabinoid degradation. These new tools have enabled the study of the physiological roles played by the endocannabinoids and have opened up new strategies in the treatment of pain, obesity, neurological diseases including multiple sclerosis, emotional disturbances such as anxiety and other psychiatric disorders including drug addiction. Recent advances have specifically linked the endogenous cannabinoid system to alcoholism, and cannabinoid receptor antagonism now emerges as a promising therapeutic alternative for alcohol dependence and relapse.”

CONCLUSION

“Since the discovery of anandamide, the increasing information on the physiological roles played by the endogenous cannabinoid system and its contribution to pathology have led to this signalling system becoming more important in neurobiology. The intense pharmacological research based on this information has yielded, in a very short time, potent, selective drugs targeting the endogenous cannabinoid system that have opened up new avenues for the understanding and treatment of major diseases including cancer, pain, neurodegeneration, anxiety and addiction. This is a very promising starting point for a new age that takes over from the ancient use of Cannabis as a medicine. Now is the time for clinical trials aimed at evaluating the efficacy of cannabinoid drugs in disorders lacking effective therapeutic approaches, such as alcoholism.”

http://alcalc.oxfordjournals.org/content/40/1/2.long