Tag Archives: antagonists

A study of cannabinoid-1 receptors during the early phase of excitotoxic damage to rat spinal locomotor networks in vitro.

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“Endocannabinoids acting on cannabinoid-1 receptors (CB1Rs) are proposed to protect brain and spinal neurons from excitotoxic damage.

The ability to recover from spinal cord injury (SCI), in which excitotoxicity is a major player, is usually investigated at late times after modulation of CB1Rs whose role in the early phases of SCI remains unclear.

Using the rat spinal cord in vitro as a model for studying SCI initial pathophysiology, we investigated if agonists or antagonists of CB1Rs might affect SCI induced by the excitotoxic agent kainate (KA) within 24 h from a transient (1 h) application of this glutamate agonist.

The present data indicate that the early phases of excitotoxic SCI could not be arrested by pharmacologically exploiting the endocannabinoid system, consistent with the notion that AEA and its derivatives are more useful to treat late SCI phases.”

http://www.ncbi.nlm.nih.gov/pubmed/27450568

Allosteric modulation of heterodimeric G-protein-coupled receptors.

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“G-protein-coupled receptors (GPCRs) are, and will probably remain, the most tractable class of targets for the development of small-molecule therapeutic medicines.

Currently, all approved GPCR-directed medicines are agonists or antagonists at orthosteric binding sites – except for the calcimimetic cinacalcet, which is a positive allosteric modulator of Ca(2+)-sensing receptors, and maraviroc, an allosteric inhibitor of CC-chemokine receptor (CCR) 5.

It is now widely accepted that GPCRs exist and might function as dimers, and there is growing evidence for the physiological presence and relevance of GPCR heterodimers.

Molecules that can regulate a GPCR within a heterodimer, through allosteric effects between the two protomers of the dimer or between a protomer or protomers and the associated G protein, offer the potential to function in a highly selective and tissue-specific way.

Despite the conceptual attraction of such allosteric regulators of GPCR heterodimers as drugs, they cannot be identified by screening approaches that routinely use a ‘one GPCR target at a time’ strategy.

In our opinion, this will require the development of new approaches for screening and a return to the use of physiologically relevant cell systems at an early stage in compound identification.”

http://www.ncbi.nlm.nih.gov/pubmed/18022255

Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors.

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“Delta9-tetrahydrocannabinol (delta9-THC), cannabinol and cannabidiol are three important natural cannabinoids from the Marijuana plant (Cannabis sativa).

Using [35S]GTP-gamma-S binding on rat cerebellar homogenate as an index of cannabinoid receptor activation we show that: delta9-THC does not induce the maximal effect obtained by classical cannabinoid receptor agonists such as CP55940.

Moreover at high concentration delta9-THC exhibits antagonist properties.

Cannabinol is a weak agonist on rat cerebellar cannabinoid receptors and cannabidiol behaves as an antagonist acting in the micromolar range.”

http://www.ncbi.nlm.nih.gov/pubmed/9667767

Cannabinoid receptors in the kidney.

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“The endocannabinoid system modulates cell signaling targets that are essential for energy homeostasis. Endocannabinoids bind to G protein-coupled receptors in the central nervous system and periphery, including the kidney. Modulation of cannabinoid receptor 1 (CB1) and CB2 activity in the kidney in diabetes and obesity has been identified as potential therapeutic target to reduce albuminuria and renal fibrosis.

CB1 and CB2 have been reported to play key roles in renal function and dysfunction. Recent studies have determined that antagonism of CB1 and agonism of CB2 in diabetic nephropathy and obesity associated kidney disease can reduce albuminuria, potentially by acting on both the glomeruli and tubules. Emerging studies have also identified a role for CB1 in renal diseases associated with fibrosis, with CB1 upregulated in multiple models of human nephropathies.

Emerging studies using isolated cells, rodent models, and human studies have identified a critical role for the endocannabinoid system in renal function and disease. Thus, therapeutics that modulate the activity of CB1 and CB2 in renal disease could become clinically relevant.”

http://www.ncbi.nlm.nih.gov/pubmed/27367912

 

Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders.

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“Agents acting via cannabinoid receptors have been widely developed; starting from the chemical structure of phytocannabinoids isolated from cannabis sativa plant, specific and selective compounds of these receptors have been produced ranging from partial to full agonists and /or antagonists endowed with different potency.

The enhanced interest on developing such classes of drugs is due to the beneficial properties widely reported by both anecdotal reports and scientific studies describing the potential medicinal use of cannabinoids and their derivatives in numerous pathological conditions in both in vitro and in vivo models.

The use of these drugs has been found to be of benefit in a wide number of neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases, just to mention some.

In particular, being the cannabinoid CB1 receptor a central receptor expressed by neurons of the central nervous system, the attention for the treatment of neurological diseases has been mainly focused on compounds acting via this receptor, however some of these compounds has been showed to act by alternative pathways in some cases unrelated to CB1 receptors.

Nonetheless, endocannabinoids are potent regulators of the synaptic function in the central nervous system and their levels are modulated in neurological diseases.

In this study, we focused on endocannabinoid mechanism of action in neuronal signaling and on cannabimimetic drug potential application in neurological disorders.

Finally, novel patents on cannabis-based drugs with applicability in central nervous system disorders are highlighted, to suggest future potential therapeutic utility of derivatives of this ancient plant.”

http://www.ncbi.nlm.nih.gov/pubmed/27334611

CB1 Receptor Antagonism Prevents Long-Term Hyperexcitability after Head Injury by Regulation of Dynorphin-KOR System and mGluR5 in Rat Hippocampus.

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“Both endocannabinoids and dynorphin are feedback messengers in nervous system that act at the presynaptic nerve terminal to inhibit transmitter release. Many studies showed the cannabinoid-opioid cross-modulation in antinociception, hypothermia, sedation and reward.

The aim of this study was to assess the influence of early application of cannabinoid type 1 (CB1) receptor antagonism SR141716A after brain injury on dynorphin-κ opioid receptor (KOR) system and the expression of metabotropic glutamate receptors (mGluRs) in a rat model of fluid percussion injury (FPI).

Firstly, seizure latency induced by pentylenetetrazole was significantly prolonged 6 weeks after brain injury in group of SR141716A treatment. Then, PCR and western blot showed that SR141716A inhibited the long-term up-regulation of CB1 receptors in hippocampus. However, SR141716A resulted in long-term potentiation of dynorphin release and did not influence the up-regulation of KOR in hippocampus after brain injury. Furthermore, SR141716A reverse the overexpression of mGluR5 in the late stage of brain injury.

We propose that during the induction of epileptogenesis after brain injury, early application of CB1 receptor antagonism could prevent long-term hyperexcitability by up-regulation of dynorphin-KOR system and prevention of mGluR5 induced epileptogenesis in hippocampus.”

http://www.ncbi.nlm.nih.gov/pubmed/27262683

Protocol to Study β-Arrestin Recruitment by CB1 and CB2 Cannabinoid Receptors.

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“Cannabinoid CB1 and CB2 receptors are G-protein-coupled receptors (GPCRs) that recruit β-arrestins upon activation by (partial) agonists. β-Arrestin recruitment is induced by phosphorylation of their C-terminal tails, and is associated with the termination of GPCR signaling; yet, it may also activate cellular signaling pathways independent of G-proteins. Here, we describe a detailed protocol to characterize the potency and efficacy of ligands to induce or inhibit β-arrestin recruitment to the human CB1 and CB2 receptors, by using the PathHunter(®) assay. The latter is a cellular assay that can be performed in plates with 384-wells. The PathHunter(®) assay makes use of β-galactosidase complementation, and has a chemiluminescent readout. We used this assay to characterize a set of reference ligands (both agonists and antagonists) on human CB1 and CB2 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27245896

The Cyclic AMP Assay Using Human Cannabinoid CB2 Receptor-Transfected Cells.

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“The cyclic AMP assay is a functional assay that is commonly used to determine the pharmacological behavior (agonists, antagonists, inverse agonists) of G-protein-coupled receptor (GPCR) ligands. Here, we describe the cyclic AMP assay that is carried out with commercially available non-radioligand ready-to-use kits and Chinese hamster ovarian (CHO) cells stably transfected with the human cannabinoid CB2 receptor.”

http://www.ncbi.nlm.nih.gov/pubmed/27245894

Cannabinoid receptor 2 (CB2) agonists and antagonists: a patent update.

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“Modulation of the CB2 receptor is an interesting approach for pain and inflammation, arthritis, addictions, neuroprotection, and cancer, among other possible therapeutic applications, and is devoid of central side effects.

Structural diversity of CB2 modulator scaffolds characterized the patent literature.

Several CB2 agonists reached clinical Phase II for pain management and inflammation.

Other therapeutic applications need to be explored such as neuroprotection and/or neurodegeneration.”

http://www.ncbi.nlm.nih.gov/pubmed/27215781

Anti-inflammatory and antioxidant effects of a combination of cannabidiol and moringin in LPS-stimulated macrophages.

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“Inflammatory response plays an important role in the activation and progress of many debilitating diseases. Natural products, like cannabidiol, a constituent of Cannabis sativa, and moringin, an isothiocyanate obtained from myrosinase-mediated hydrolysis of the glucosinolate precursor glucomoringin present in Moringa oleifera seeds, are well known antioxidants also endowed with anti-inflammatory activity.

This is due to a covalent-based mechanism for ITC, while non-covalent interactions underlie the activity of CBD. Since these two mechanisms are distinct, and the molecular endpoints are potentially complementary, we investigated in a comparative way the protective effect of these compounds alone or in combination on lipopolysaccharide-stimulated murine macrophages.

Our results show that the cannabidiol (5μM) and moringin (5μM) combination outperformed the single constituents that, at this dosage had only a moderate efficacy on inflammatory (Tumor necrosis factor-α, Interleukin-10) and oxidative markers (inducible nitric oxide synthase, nuclear factor erythroid 2-related factor 2, nitrotyrosine). Significant upregulation of Bcl-2 and downregulation of Bax and cleaved caspase-3 was observed in cells treated with cannabidiol-moringin combination.

Treatment with the transient receptor potential vanilloid receptor 1 antagonist was detrimental for the efficacy of cannabidiol, while no effect was elicited by cannabinoid receptor 1 and cannabinoid receptor 2 antagonists. None of these receptors was involved in the activity of moringin.

Taken together, our in vitro results testify the anti-inflammatory, antioxidative, and anti-apoptotic effects of the combination of cannabidiol and moringin.”

http://www.ncbi.nlm.nih.gov/pubmed/27215129