Tag Archives: antagonists

Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands.

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“The available commercial cannabinoids have a narrow therapeutic index. Recently developed peripherally restricted cannabinoids, regionally administered cannabinoids, bifunctional cannabinoid ligands and cannabinoid enzyme inhibitors, endocannabinoids, which do not interact with classic cannabinoid receptors (CB1r and CB2r), cannabinoid receptor antagonists and selective CB1r agonists hold promise as analgesics…

Expert opinion: Regional and peripherally restricted cannabinoids will reduce cannabinomimetic side effects. Spinal cannabinoids may increase the therapeutic index by limiting the dose necessary for response and minimize drugs exposure to supraspinal sites where cannabinomimetic side effects originate. Cannabinoid bifunctional ligands should be further explored. The combination of a CB2r agonist with a transient receptor potential vanilloid (TRPV-1) antagonist may improve the therapeutic index of the CB2r agonist. Enzyme inhibitors plus TRPV-1 blockers should be further explored. The development of analgesic tolerance with enzyme inhibitors and the pronociceptive effects of prostamides limit the benefits to cannabinoid hydrolyzing enzyme inhibitors.

Most clinically productive development of cannabinoids over the next 5 years will be in the area of selective CB2r agonists. These agents will be tested in various inflammatory, osteoarthritis and neuropathic pains.”

http://www.ncbi.nlm.nih.gov/pubmed/24836296

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

Combining rimonabant and fentanyl in a single entity: preparation and pharmacological results.

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“Based on numerous pharmacological studies that have revealed an interaction between cannabinoid and opioid systems at the molecular, neurochemical, and behavioral levels, a new series of hybrid molecules has been prepared by coupling the molecular features of two wellknown drugs, ie, rimonabant and fentanyl. The new compounds have been tested for their affinity and functionality regarding CB1 and CB2 cannabinoid and μ opioid receptors. In [(35)S]-GTPγS (guanosine 5′-O-[gamma-thio]triphosphate) binding assays from the post-mortem human frontal cortex, they proved to be CB1 cannabinoid antagonists and μ opioid antagonists. Interestingly, in vivo, the new compounds exhibited a significant dual antagonist action on the endocannabinoid and opioid systems.”

http://www.ncbi.nlm.nih.gov/pubmed/24591816

Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis users and psychosis: a critical review.

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“…different cannabis compounds may exert opposite effects on the neuroanatomical changes underlying psychosis. In particular, cannabidiol (CBD) was shown to prevent THC associated hippocampal volume loss… This finding is further supported by several animal experiments supporting neuroprotective properties of CBD mainly via anti-oxidative effects, CB2 receptors or adenosine receptors… mechanisms by which CBD may reduce brain volume loss, including antagonism of THC, interactions with endocannabinoids, and mechanisms that specifically underlie antipsychotic properties of CBD.”

http://www.ncbi.nlm.nih.gov/pubmed/22716143

Unique effects of compounds active at both cannabinoid and serotonin receptors during stroke.

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“We reported previously that both a cannabinoid receptor 2 (CB2R) agonist and a cannabinoid receptor 1 (CB1R) antagonist were protective in the treatment of transient middle cerebral artery occlusion/reperfusion injury (MCAO/R) and that they acted in a synergistic manner when administered in combination. The goal of the current study was to determine which of the potential cannabinoid receptors participate in the protective effects of this drug combination in a mouse model of MCAO/R.

The effects of administration of the CB2R agonist/CB1R antagonist combination on infarct size and cerebral blood flow during a 1-h occlusion were tested…

In conclusion, administration of the CB2R agonist/CB1R antagonist combination causes a significant reduction in infarct size in the MCAO/R model. The protective effect involves both the CB2R and the 5-HT1A receptor. Neither the CB1R nor the TRPV1 receptors appear to participate in this response.”

http://www.ncbi.nlm.nih.gov/pubmed/24323810

Evaluation of the role of striatal cannabinoid CB1 receptors on movement activity of parkinsonian rats induced by reserpine.

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“It has been observed cannabinoid CB1 receptor signalling and the levels of endocannabinoid ligands significantly increased in the basal ganglia and cerebrospinal fluids of Parkinson’s disease (PD) patients. These evidences suggest that the blocking of cannabinoid CB1 receptors might be beneficial to improve movement disorders as a sign of PD…

 These results support this theory that cannabinoid CB1 receptor antagonists might be useful to alleviate movement disorder in PD…”

http://www.ncbi.nlm.nih.gov/pubmed/23960729

Evaluation of the potential of the phytocannabinoids, cannabidivarin (CBDV) and Δ9 -tetrahydrocannabivarin (THCV), to produce CB1 receptor inverse agonism symptoms of nausea in rats.

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“The cannabinoid 1(CB1 ) receptor inverse agonists/antagonists, rimonabant (SR141716, SR) and AM251, produce nausea and potentiate toxin-induced nausea by inverse agonism (rather than antagonism) of the CB1 receptor. Here, we evaluated two phytocannabinoids, cannabidivarin (CBDV) and Δ9 -tetrahydrocannabivarin (THCV) for their ability to produce these behavioural effects characteristic of CB1 receptor inverse agonism in rats.

…we investigated the potential of THCV and CBDV to produce conditioned gaping (measure of nausea-induced behaviour),..

THC, THCV  and CBDV suppressed LiCl-induced conditioned gaping, suggesting anti-nausea potential…

The pattern of findings indicates that neither THCV nor CBDV produced a behavioural profile characteristic of CB1 receptor inverse agonists.

As well, these compounds may have therapeutic potential in reducing nausea.”

http://www.ncbi.nlm.nih.gov/pubmed/23902479

Peripherally restricted CB1 receptor blockers.

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“Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease.

These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists.

Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed.

Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).”

http://www.ncbi.nlm.nih.gov/pubmed/23902803

The endocannabinoid system in advanced liver cirrhosis: pathophysiological implication and future perspectives.

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“Endogenous cannabinoids (EC) are ubiquitous lipid signalling molecules providing different central and peripheral effects that are mediated mostly by the specific receptors CB1 and CB2. The EC system is highly upregulated during chronic liver disease and consistent experimental and clinical findings indicate that it plays a role in the pathogenesis of liver fibrosis and fatty liver disease associated with obesity, alcohol abuse and hepatitis C.

Furthermore, a considerable number of studies have shown that EC and their receptors contribute to the pathogenesis of the cardio-circulatory disturbances occurring in advanced cirrhosis, such as portal hypertension, hyperdynamic circulatory syndrome and cirrhotic cardiomyopathy.

More recently, the EC system has been implicated in the development of ascites, hepatic encephalopathy and the inflammatory response related to bacterial infection. Rimonabant, a selective CB1 antagonist, was the first drug acting on the EC system approved for the treatment of obesity. Unfortunately, it has been withdrawn from the market because of its neuropsychiatric side effects.

Compounds able to target selectively the peripheral CB1 receptors are under evaluation.

In addition, molecules stimulating CB2 receptor or modulating the activity of enzymes implicated in EC metabolism are promising areas of pharmacological research.

Liver cirrhosis and the related complications represent an important target for the clinical application of these compounds.”

http://www.ncbi.nlm.nih.gov/pubmed/23890208

The role of CB1 in immune modulation by cannabinoids.

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“There is clear evidence that CB(2), historically referred to as the peripheral cannabinoid receptor, mediates many of the immune modulatory effects of cannabinoids.

 However, cannabinoid receptors cannot be classified simply as central or peripheral since CB(2) has been shown to play a role in the central nervous system (CNS) and CB(1) mediates many immune system effects. Although Cnr1 mRNA and CB(1) protein expression is lower than Cnr2 mRNA or CB(2) protein expression in cells of the immune system, several studies have shown direct modulation of immune function via CB(1) by endogenous and exogenous cannabinoids in T cells, innate cells, and to a lesser extent, B cells.

In addition, indirect, but CB(1)-dependent, mechanisms of immune modulation exist. In fact, the mechanism by which cannabinoids attenuate neuroinflammation via CB(1) is likely a combination of immune suppression and neuroprotection.

 Although many studies demonstrate that agonists for CB(1) are immune suppressive and anti-inflammatory, CB(1) antagonists also exhibit anti-inflammatory properties. Overall, the data demonstrate that many of the immune modulatory effects of cannabinoids are mediated via CB(1).”

http://www.ncbi.nlm.nih.gov/pubmed/23261520

The cannabinoid Δ9-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity

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“Δ9-Tetra-hydrocannabivarin (THCV) is a naturally occurring analogue of the psychoactive principle of cannabis, Δ9-tetra-hydrocannabinol (THC).

THCV is a new potential treatment against obesity-associated glucose intolerance with pharmacology different from that of CB1 inverse agonists/antagonists.

In conclusion, THCV produces therapeutic metabolic effects in two different mouse models of obesity. In particular, its strongest effects are exerted on plasma glucose and insulin levels, especially following an OGTT in DIO mice and on liver triglycerides in ob/obmice.

Based on these data, it can be suggested that THCV may be useful for the treatment of the metabolic syndrome and/or type 2 diabetes, either alone or in combination with existing treatments. Given the reported benefits of another non-THC cannabinoid, CBD in type 1 diabetes, a CBD/THCV combination may be beneficial for different types of diabetes mellitus.”

Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671751/