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Cannabinoid Receptor Antagonist (cannabinoid + receptor_antagonist)
Selected AbstractsA critical review of the cannabinoid receptor as a drug target for obesity managementOBESITY REVIEWS, Issue 1 2009F. Akbas Summary The discovery of cannabinoids, with the well-known stimulatory effect of Cannabis sativa on appetite, has offered a new drug target for obesity treatment. Cannabinoids act on two different receptors: CB1 receptors which are sited in the brain and many peripheral tissues, and CB2 receptors which are primarily found in immune system cells. Cannabinoid receptor antagonists act centrally by blocking CB1 receptors, thereby reducing food intake. Moreover, they probably also act peripherally by increasing thermogenesis and therefore energy expenditure, as has been suggested by animal experiments. Despite these promising mechanisms of action, recent clinical studies examining the effect of the two CB1 receptor antagonists rimonabant and taranabant showed that the attained weight loss did not exceed that attained with other currently approved anti-obesity medications. Moreover, potentially severe psychiatric adverse effects limit their clinical use. As several new CB1 receptor antagonists are presently undergoing development, it remains to be elucidated to what extent they differ in terms of efficacy and safety. This review primarily discusses how close cannabinoid receptor antagonists are to the ideal anti-obesity drug, with respect to their mechanisms of action, clinical effectiveness and safety. [source] New therapies available for the treatment of type 2 diabetesEUROPEAN DIABETES NURSING, Issue 2 2006C Day PhD Visiting Fellow Abstract Summary In type 2 diabetes multiple lesions have been identified; new drugs are being developed that target these lesions. This review considers the most recent pharmaceutical options to reduce hyperglycaemia. Two new classes of agents were introduced in the USA in 2005, both of which are administered by injection. The first agent, pramlintide, is a soluble analogue of the islet peptide amylin which is used as an adjunct to insulin therapy. Exenatide is an analogue of the incretin hormone GLP-1 and has similar actions to native GLP-1. Both agents reduce hyperglycaemia without causing weight gain and can aid weight loss. A cannabinoid receptor antagonist (rimonabant) which aids weight loss and improves glycaemic control in type 2 diabetes has recently received marketing approval as an antiobesity agent in Europe. The gliptins and glitazars are at advanced stages of development and fixed-dose combination ,2.4.1' tablets containing established agents are being introduced. Copyright © 2006 FEND. [source] The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxietyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2002J. Haller Abstract The aim of this study was to compare the effects of the genetic and pharmacological disruption of CB1 cannabinoid receptors on the elevated plus-maze test of anxiety. In the first experiment, the behaviour of CB1-knockout mice and wild-type mice was compared. In the second experiment, the cannabinoid antagonist SR141716A (0, 1, and 3 mg/kg) was administered to both CB1-knockout and wild type mice. Untreated CB1-knockout mice showed a reduced exploration of the open arms of the plus-maze apparatus, thus appearing more anxious than the wild-type animals, however no changes in locomotion were noticed. The vehicle-injected CB1-knockout mice from the second experiment also showed increased anxiety as compared with wild types. Surprisingly, the cannabinoid antagonist SR141716A reduced anxiety in both wild type and CB1 knockout mice. Locomotor behaviour was only marginally affected. Recent evidence suggests the existence of a novel cannabinoid receptor in the brain. It has also been shown that SR141716A binds to both the CB1 and the putative novel receptor. The data presented here supports these findings, as the cannabinoid receptor antagonist affected anxiety in both wild type and CB1-knockout mice. Tentatively, it may be suggested that the discrepancy between the effects of the genetic and pharmacological blockade of the CB1 receptor suggests that the novel receptor plays a role in anxiety. [source] The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptorsFEBS JOURNAL, Issue 7 2001Tiziana Bisogno It is not yet clear if the endocannabinoid 2-arachidonoylglycerol (2-AG) is transported into cells through the same membrane transporter mediating the uptake of the other endogenous cannabinoid, anandamide (N -arachidonoylethanolamine, AEA), and whether this process (a) is regulated by cells and (b) limits 2-AG pharmacological actions. We have studied simultaneously the facilitated transport of [14C]AEA and [3H]2-AG into rat C6 glioma cells and found uptake mechanisms with different efficacies but similar affinities for the two compounds (Km 11.0 ± 2.0 and 15.3 ± 3.1 µm, Bmax 1.70 ± 0.30 and 0.24 ± 0.04 nmol·min,1·mg protein,1, respectively). Despite these similar Km values, 2-AG inhibits [14C]AEA uptake by cells at concentrations (Ki = 30.1 ± 3.9 µm) significantly higher than those required to either 2-AG or AEA to inhibit [3H]2-AG uptake (Ki = 18.9 ± 1.8 and 20.5 ± 3.2 µm, respectively). Furthermore: (a) if C6 cells are incubated simultaneously with identical concentrations of [14C]AEA and [3H]2-AG, only the uptake of the latter compound is significantly decreased as compared to that observed with [3H]2-AG alone; (b) the uptake of [14C]AEA and [3H]2-AG by cells is inhibited with the same potency by AM404 (Ki = 7.5 ± 0.7 and 10.2 ± 1.7 µm, respectively) and linvanil (Ki = 9.5 ± 0.7 and 6.4 ± 1.2 µm, respectively), two inhibitors of the AEA membrane transporter; (c) nitric oxide (NO) donors enhance the uptake of both [14C]AEA and [3H]2-AG, thus suggesting that 2-AG action can be regulated through NO release; (d) AEA and 2-AG induce a weak release of NO that can be blocked by a CB1 cannabinoid receptor antagonist, and significantly enhanced in the presence of AM404 and linvanil, thus suggesting that transport into C6 cells limits the action of both endocannabinoids. [source] Selective CB1 cannabinoid receptor antagonist, SR141716A, attenuates liver injury induced by Concanavalin AHEPATOLOGY RESEARCH, Issue 4 2009Midori Kojima Aim:, The aim of this study was to investigate the hepatoprotective activity of a selective cannabinoid receptor 1 (CB1) antagonist, SR141716A, in a Concanavalin A (Con A)-induced mouse liver injury model and to determine whether SR141716A has an effect on the production of inflammatory cytokines and chemokines induced by Con A. Results:, Injection of Con A (20 mg/kg) to mice developed hepatitis determined by plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation and necrosis in the liver. Pretreatment with SR141716A (30 mg/kg) significantly reduced plasma AST and ALT level, protected against necrosis in the liver, and significantly reduced plasma cytokine and chemokine levels, including TNF,, IFN-,, CXCL9, MIP1-,, and IL-10 and no change decreased in IL-4. Conclusions:, The selective CB1 antagonist, SR141716A, exerts a hepatoprotective effect on Con A-induced liver injury in mice by attenuating the increase in cytokine and chemokine levels and inhibiting hepatocyte injury. These findings raise the possibility of using CB1 antagonists as anti-inflammatory drugs for treating hepatitis as well as other inflammatory diseases. [source] Anandamide-induced relaxation of sheep coronary arteries: the role of the vascular endothelium, arachidonic acid metabolites and potassium channelsBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2001J Grainger The effects of the endocannabinoid, anandamide, and its metabolically stable analogue, methanandamide, on induced tone were examined in sheep coronary artery rings in vitro. In endothelium-intact rings precontracted to the thromboxane A2 mimetic, U46619, anandamide (0.01 , 30 ,M) induced slowly developing concentration-dependent relaxations (pEC50 [negative log of EC50]=6.1±0.1; Rmax [maximum response]=81±4%). Endothelium denudation caused a 10 fold rightward shift of the anandamide concentration-relaxation curve without modifying Rmax. Methanandamide was without effect on U46619-induced tone. The anandamide-induced relaxation was unaffected by the cannabinoid receptor antagonist, SR 141716A (3 ,M), the vanilloid receptor antagonist, capsazepine (3 and 10 ,M) or the nitric oxide synthase inhibitor, L -NAME (100 ,M). The cyclo-oxygenase inhibitor, indomethacin (3 and 10 ,M) and the anandamide amidohydrolase inhibitor, PMSF (70 and 200 ,M), markedly attenuated the anandamide response. The anandamide transport inhibitor, AM 404 (10 and 30 ,M), shifted the anandamide concentration-response curve to the right. Precontraction of endothelium-intact rings with 25 mM KCl attenuated the anandamide-induced relaxations (Rmax=7±7%), as did K+ channel blockade with tetraethylammonium (TEA; 3 ,M) or iberiotoxin (100 nM). Blockade of small conductance, Ca2+ -activated K+ channels, delayed rectifier K+ channels, KATP channels or inward rectifier K+ channels was without effect. These data suggest that the relaxant effects of anandamide in sheep coronary arteries are mediated in part via the endothelium and result from the cellular uptake and conversion of anandamide to a vasodilatory prostanoid. This, in turn, causes vasorelaxation, in part, by opening potassium channels. British Journal of Pharmacology (2001) 134, 1003,1012; doi:10.1038/sj.bjp.0704340 [source] 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 useJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2007S. Xie Pharm D student Summary 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 CB1 (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. [source] A critical review of the cannabinoid receptor as a drug target for obesity managementOBESITY REVIEWS, Issue 1 2009F. Akbas Summary The discovery of cannabinoids, with the well-known stimulatory effect of Cannabis sativa on appetite, has offered a new drug target for obesity treatment. Cannabinoids act on two different receptors: CB1 receptors which are sited in the brain and many peripheral tissues, and CB2 receptors which are primarily found in immune system cells. Cannabinoid receptor antagonists act centrally by blocking CB1 receptors, thereby reducing food intake. Moreover, they probably also act peripherally by increasing thermogenesis and therefore energy expenditure, as has been suggested by animal experiments. Despite these promising mechanisms of action, recent clinical studies examining the effect of the two CB1 receptor antagonists rimonabant and taranabant showed that the attained weight loss did not exceed that attained with other currently approved anti-obesity medications. Moreover, potentially severe psychiatric adverse effects limit their clinical use. As several new CB1 receptor antagonists are presently undergoing development, it remains to be elucidated to what extent they differ in terms of efficacy and safety. This review primarily discusses how close cannabinoid receptor antagonists are to the ideal anti-obesity drug, with respect to their mechanisms of action, clinical effectiveness and safety. [source] | ||||||||||