Tag Archives: cannabinoid receptors

Therapeutic potential of endocannabinoid-hydrolysing enzyme inhibitors.

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Abstract

“The specific protein target of delta9-tetrahydrocannabinol (delta9-THC), the main active ingredient of Cannabis sativa L., was characterized from rat brain nearly 20 years ago, and several endogenous compounds and proteins comprising the endocannabinoid (eCB) system have since been discovered. It has become evident that the eCB system consists of at least two cannabinoid receptors (i.e. the CB1 and CB2 receptors), in addition to their endogenous ligands (the eCBs) and several enzymes involved in the biosynthesis and catabolism of the eCBs. The two well-established eCBs, N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced by neurons on demand, act near their sites of synthesis and are effectively metabolized by fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL), respectively. Inhibitors specifically targeting these enzymes could offer novel therapeutic approaches (e.g. for the treatment of pain and movement disorders). This MiniReview summarizes the literature concerning the potential therapeutic potential of FAAH and MGL inhibitors.”

http://www.ncbi.nlm.nih.gov/pubmed/17910610

Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors.

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Abstract

“Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are hydrolytic enzymes which degrade the endogenous cannabinoids (endocannabinoids) N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), respectively. Endocannabinoids are an important class of lipid messenger molecules that are produced on demand in response to elevated intracellular calcium levels. They recognize and activate the cannabinoid CB(1) and CB(2) receptors, the molecular targets for Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in marijuana evoking several beneficial therapeutic effects. However, in vivo the cannabimimetic effects of AEA and 2-AG remain weak owing to their rapid inactivation by FAAH and MGL, respectively. The inactivation of FAAH and MGL by specific enzyme inhibitors increases the levels of AEA and 2-AG, respectively, producing therapeutic effects such as pain relief and depression of anxiety.”

http://www.ncbi.nlm.nih.gov/pubmed/20370710

A new strategy to block tumor growth by inhibiting endocannabinoid inactivation.

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“Endocannabinoid signaling has been shown to be enhanced in several cancer tissues and malignant cells, and studies in cell lines have shown that this up-regulation might serve the purpose of providing transformed cells with a further means to inhibit their proliferation. Here we investigated the effect of inhibitors of endocannabinoid degradation on the growth of rat thyroid tumor xenografts induced in athymic mice. VDM-11, a selective inhibitor of endocannabinoid cellular re-uptake, and arachidonoyl-serotonin (AA-5-HT), a selective blocker of endocannabinoid enzymatic hydrolysis, both inhibited the growth in vivo of tumor xenografts induced by the subcutaneous injection of rat thyroid transformed (KiMol) cells. This effect was accompanied by significantly enhanced endocannabinoid concentrations in the tumors excised at the end of the in vivo experiments. Endocannabinoids, as well as VDM-11 and AA-5-HT, inhibited the growth in vitro of the transformed rat thyroid cells used to induce the tumors in vivo, and their effect was reversed at least in part by the cannabinoid CB1 receptor antagonist SR141716A. This compound, however, when administered alone, did not enhance, but instead slightly inhibited, the growth of rat thyroid transformed cells both in vitro and in tumor xenografts induced in vivo. These findings indicate that endocannabinoids tonically control tumor growth in vivo by both CB1-mediated and non-CB1-mediated mechanisms and that, irrespective of the molecular mechanism of their anti-proliferative action, inhibitors of their inactivation might be used for the development of novel anti-cancer drugs.”  http://www.ncbi.nlm.nih.gov/pubmed/15289448

“A new strategy to block tumor growth by inhibiting endocannabinoid inactivation”  http://www.fasebj.org/content/early/2004/10/02/fj.04-1754fje.long

A metabolically stable analogue of anandamide, Met-F-AEA, inhibits human thyroid carcinoma cell lines by activation of apoptosis.

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Abstract

  “The active components of Cannabis sativa and their derivatives produce a wide spectrum of effects, some of which may have clinical application. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids as agents capable of controlling the decision of cells to survive or die. We analysed the effects exerted by 2-methyl-2′-F-anandamide (Met-F-AEA), a metabolically stable analogue of anandamide, and observed a growth inhibition in cell lines derived from thyroid carcinomas. Growth inhibition was associated with a high level of CB1 receptor expression, suggesting that the cytotoxic effect is due to interaction with the CB1 receptor. This phenomenon was associated with activation of the protein, p53, an increased apoptotic rate, and expression of p21(CIP1/WAF1). This study provides new insights into the mechanism of Met-F-AEA action, and could have significance in providing a basis for the management of thyroid carcinoma.”

http://www.ncbi.nlm.nih.gov/pubmed/19189054

Endogenous cannabinoids and neutrophil chemotaxis.

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Abstract

  “Neutrophils are the earliest inflammatory cell to infiltrate tissue, playing an important role in early phagocytosis. Under pathological conditions, pro-inflammatory actions of neutrophils contribute to the development of various inflammatory diseases. G(i) protein-coupled cell-surface receptors are an essential component of pro-migratory responses in leukocytes; however, few investigations regarding inhibitors of cell migration have been reported. Kurihara et al. (2006) and McHugh et al. (2008) have revealed that certain endogenous cannabinoids and lipids are potent inhibitors of induced human neutrophil migration. McHugh et al. implicate a novel SR141716A-sensitive pharmacological target distinct from cannabinoid CB(1) and CB(2) receptors, which is antagonized by N-arachidonoyl-l-serine; and that the CB(2) receptor exerts negative co-operativity upon this receptor. Kurihara et al. demonstrate that fMLP-induced RhoA activity is decreased following endocannabinoid pretreatment, disrupting the front/rear polarization necessary for neutrophils to engage in chemotaxis.

The therapeutic potential of exploiting endocannabinoids as neutrophilic chemorepellants is plain to see.”

http://www.ncbi.nlm.nih.gov/pubmed/19647118

Inhibition of Human Neutrophil Chemotaxis by Endogenous Cannabinoids and Phytocannabinoids: Evidence for a Site Distinct from CB1 and CB2

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   “Here, we show a novel pharmacology for inhibition of human neutrophil migration by endocannabinoids, phytocannabinoids, and related compounds. The endocannabinoids virodhamine and N-arachidonoyl dopamine are potent inhibitors of N-formyl-l-methionyl-l-leucyl-l-phenylalanine-induced migration of human neutrophils…”

   “This study reveals that certain endogenous lipids, phytocannabinoids and related ligands are potent inhibitors of human neutrophil migration, and it implicates a novel pharmacological target distinct from cannabinoid CB1 and CB2 receptors; this target is antagonized by the endogenous compound N-arachidoloyl l-serine. These findings corroborate the emerging clinical and animal model data demonstrating that the nonpsychoactive phytocannabinoid, CBD and its structural analogs are effective in alleviating arthritis. Furthermore, our findings have implications for the potential pharmacological manipulation of elements of the endocannabinoid system for the treatment of various inflammatory conditions.”

http://molpharm.aspetjournals.org/content/73/2/441.long

Naturally occurring and related synthetic cannabinoids and their potential therapeutic applications.

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Abstract

“Naturally occurring cannabinoids (phytocannabinoids) are biosynthetically related terpenophenolic compounds uniquely produced by the highly variable plant, Cannabis sativa L. Natural and synthetic cannabinoids have been extensively studied since the discovery that the psychotropic effects of cannabis are mainly due to Delta(9)-THC. However, cannabinoids exert pharmacological actions on other biological systems such as the cardiovascular, immune and endocrine systems. Most of these effects have been attributed to the ability of these compounds to interact with the cannabinoid CB1 and CB2 receptors. The FDA approval of Marinol, a product containing synthetic Delta(9)-THC (dronabinol), in 1985 for the control of nausea and vomiting in cancer patients receiving chemotherapy, and in 1992 as an appetite stimulant for AIDS patients, has further intensified the research interest in these compounds. This article reviews patents (2003-2007) that describe methods for isolation of cannabinoids from cannabis, chemical and chromatographic methods for their purification, synthesis, and potential therapeutic applications of these compounds.”

http://www.ncbi.nlm.nih.gov/pubmed/19519560

Fungal biotransformation of cannabinoids: potential for new effective drugs.

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Abstract

“Phytocannabinoids from the plant Cannabis sativa induce a variety of physiological and pharmacological responses in living systems, including anti-inflammatory, antinociceptive, anti-ulcer and antitumor activities. The discovery of the cannabinoid receptors CB1 and CB2 led to the development of agonists and antagonists of these receptors for the treatment of a variety of diseases. Nabilone, a synthetic derivative of Delta9-tetrahydrocannabinol (Delta9-THC), which is the main natural psychotropic constituent of C sativa, was approved by the US FDA for the treatment of nausea and as an anti-emetic for patients undergoing chemotherapy. Delta9-THC and related cannabinoids are involved in a variety of signal transduction pathways; thus, reducing or removing the psychotropic effects of these compounds would enhance their therapeutic spectra. Compound synthesis and qualitative SAR studies are time-consuming activities; however, microbes are effectively the most inventive synthetic chemists because of their metabolic plasticity. This review discusses the potential of C sativa mycoflora, which is pathogenic as well as endophytic, to remove the psychotropic effects of Delta9-THC and related cannabinoids, and describes the development of a model system for the rapid and cost-effective commercial production of cannabinoids through fermentation pathways.”

http://www.ncbi.nlm.nih.gov/pubmed/19333876

Anti-proliferative and anti-angiogenic effects of CB2R agonist (JWH-133) in non-small lung cancer cells (A549) and human umbilical vein endothelial cells: an in vitro investigation.

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“Non-small cell lung cancer has one of the highest mortality rates among cancer-suffering patients. It is well known that the unwanted psychotropic effects of cannabinoids (CBs) are mediated via the CB(1) receptor (R), and selective targeting of the CB(2)R would thus avoid side effects in cancer treatment…

the aim of our study was to evaluate the effect of selective CB(2)R agonist, JWH-133, on A549 cells (non-small lung cancer) and human umbilical vein endothelial cells (HUVECs)…

The present study demonstrates the in vitro anti-proliferative and anti-angiogenic potential of CB(2)R agonist, JWH-133, in nonsmall lung cancer cells and HUVECs.

Our results generate a rationale for further in vivo efficacy studies with this compound in preclinical cancer models.”

http://www.ncbi.nlm.nih.gov/pubmed/22578958

Cannabinoid Receptors, CB1 and CB2, as Novel Targets for Inhibition of Non-Small Cell Lung Cancer Growth and Metastasis

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“Cannabinoid receptors are expressed in human lung cancers”

 

  “Recently, CB1 and CB2 have been shown to be overexpressed on tumor cells compared to normal cells in various types of cancers, such as breast and liver, and therefore could be used as novel targets for cancer. In addition, several cannabinoids, including THC and cannabidiol, synthetic cannabinoid-agonists JWH-133, Win55,212-2, were shown to inhibit tumor growth and progression of several types of cancers, including glioma, glioblastoma multiforme, breast, prostate, colon carcinomas, leukemia and lymphoid tumors.”

“There are three general types of cannabinoids: phytocannabinoids, THC and cannabidiol, are derived from plants; endogenous cannabinoids, 2AG and AEA, which are produced inside the body; and synthetic cannabinoids, JWH-133/JWH-015, CP-55 and Win55,212-2.”

“Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide; however, only limited therapeutic treatments are available. Hence, we investigated the role of cannabinoid receptors, CB1 and CB2, as novel therapeutic targets against NSCLC…”

“These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025486/