Cannabinoid 1 G protein-coupled receptor (periphero-)neutral antagonists: emerging therapeutics for treating obesity-driven metabolic disease and reducing cardiovascular risk

Bibliography

• Figlewicz DP, Sipols AJ. Energy regulatory signals and food reward. Pharmacol Biochem Behav 2010;97:15-24
   PubMed Web of Science ®Google Scholar
• Okorodudu DO, Jumean MF, Montori VM, Diagnostic performance of body mass index to identify obesity as defined as body adiposity: a systematic review and meta-analysis. Int J Obes 2010;34:791-9
   PubMed Web of Science ®Google Scholar
• Sørensen TIA, Virtue S, Vidal-Puig A. Obesity as a clinical and public health problem: is there a need for a new definition based on lipotoxicity effects? Biochim Biophys Acta 2010;1801:400-4
   PubMed Web of Science ®Google Scholar
• Finucane MM, Stevens GA, Cowan MJ, National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011;377:557-67
   PubMed Web of Science ®Google Scholar
• World Health Organization. Obesity and overweight. 2011. Available from: http://www.who.int/mediacentre/factsheets/fs311/en/index.html [Last accessed 21 July 2011]
   Google Scholar
• Gallagher EJ, LeRoith D. Insulin, insulin resistance, obesity, and cancer. Curr Diab Rep 2010;10:93-100
   PubMed Web of Science ®Google Scholar
• Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol Mech Dis 2010;5:145-71
   PubMed Web of Science ®Google Scholar
• Chan DC, Watts GF. Dyslipidemia in the metabolic syndrome and type 2 diabetes: pathogenesis, priorities, pharmacotherapies. Expert Opin Pharmacother 2011;12:13-30
   PubMed Web of Science ®Google Scholar
• Mottillo S, Filion KB, Genest J, The metabolic syndrome and cardiovascular risk: a systematic review and meta-analysis. J Am Coll Cardiol 2010;56:1113-32
   PubMed Web of Science ®Google Scholar
• Colagiuri S. Diabesity: therapeutic options. Diabetes Obes Metab 2010;12:463-73
   PubMed Web of Science ®Google Scholar
• Artinisan NT, Fletcher GF, Mozaffarian D, Interventions to promote physical activity and dietary lifestyle changes for cardiovascular risk factor reduction in adults. Circulation 2010;122:406-41
   PubMed Web of Science ®Google Scholar
• Astrup A. Drug management of obesity– efficacy versus safety. N Engl J Med 2010;363:288-90
   PubMed Web of Science ®Google Scholar
• Ioannides-Demos LL, Piccenna L, McNeil JJ. Pharmacotherapies for obesity: past, current, and future therapies. J Obes 2010; published online 17 December 2010; doi:10.1155/2011/179674
   PubMedGoogle Scholar
• Halford JCG, Boyalnd EJ, Blundell JE, Pharmacological management of appetite expression in obesity. Nat Rev Endocrinol 2010;6:255-69
   PubMed Web of Science ®Google Scholar
• Janero DR, Makriyannis A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin Emerg Drugs 2009;14:43-65
   PubMed Web of Science ®Google Scholar
• Wu KC, Gerstenbilith G. Update on newer antihypertensive medicines and interventions. J Cardiovasc Pharmacol Ther 2010;15:257-67
   PubMed Web of Science ®Google Scholar
• Nathan DM. Navigating the choices for diabetes prevention. N Engl J Med 2010;362:1533-5
   PubMed Web of Science ®Google Scholar
• Hauber AB, Mohamed AF, Johnson FR, Falvey H. Treatment preferences and medication adherence of people with type 2 diabetes using oral glucose-lowering agents. Diabet Med 2009;26:416-24
   PubMed Web of Science ®Google Scholar
• Van Reedt Dortland AK, Giltay EJ, van Veen T, Metabolic syndrome abnormalities are associated with severity of anxiety and depression and with tricyclic antidepressant use. Acta Psychiatr Scand 2010;122:30-9
   PubMed Web of Science ®Google Scholar
• Heal DJ, Godsen J, Smith SL. Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders. Br J Clin Pharmacol 2009;68:861-74
   PubMed Web of Science ®Google Scholar
• Boekholdt SM, Peters RJG. Rimonabant: obituary for a wonder drug. Lancet 2010;376:489-90
   PubMed Web of Science ®Google Scholar
• Koch L. Obesity: taranabant no longer developed as an antiobesity agent. Nat Rev Endocrinol 2010;6:300
   PubMedGoogle Scholar
• Di Marzo V. The endocananbinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation. Pharmacol Res 2009;60:77-84
   PubMed Web of Science ®Google Scholar
• Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol 2008;20:S10-14
   PubMed Web of Science ®Google Scholar
• Bosier B, Muccioli GG, Hermans E, Lambert DM. Functionally selective cananbinoid receptor signalling: therapeutic implications and opportunities. Biochem Pharmacol 2010;80:1-12
   PubMed Web of Science ®Google Scholar
• Turu G, Hunyady L. Signal transduction of the CB1 cannabinoid receptor. J Mol Endocrinol 2010;44:75-85
   PubMed Web of Science ®Google Scholar
• Ahn K, McKinney MK, Cravatt BF. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev 2008;108:1687-707
   PubMed Web of Science ®Google Scholar
• Maccarrone M, Gasperi V, Catani MV, The endocananbinoid system and its relevance for nutrition. Annu Rev Nutr 2010;30:423-40
   PubMed Web of Science ®Google Scholar
• Li C, Jones PM, Persaud SJ. Role of the endocannabinoid system in food intake, energy homeostasis and regulation of the endocrine pancreas. Pharmacol Ther 2011;129:307-20
   PubMed Web of Science ®Google Scholar
• Soria-Gomez E, Matias I, Rueda-Orozoco PE, Pharmacological modulation of the endocannabinoid system in the nucleus accumbens shell stimulates food intake and increases c-fos expression in the hypothalamus. Br J Pharmacol 2007;151:1109-16
   PubMed Web of Science ®Google Scholar
• Sink KS, Segovia KN, Nunes EJ, Intracerebrovascular administration of cannabinoid CB1 receptor antagonists AM251 and AM4113 fails to alter food-reinforced behavior in rats. Psychopharmacology 2009;206:223-32
   PubMed Web of Science ®Google Scholar
• Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol 2002;136:550-7
   PubMed Web of Science ®Google Scholar
• Storr MA, Sharkey KA. The endocananbinoid system and gut-brain signalling. Curr Opin Pharmacol 2007;7:575-82
   PubMed Web of Science ®Google Scholar
• Burdyga G, Varro A, Dimaline R, Expression of cannabinoid CB1 receptors by vagal afferent neurons: kinetics and role in influencing neurochemical phenotype. Am J Physiol Gastrointest Liver Physiol 2010;299:G63-9
   PubMed Web of Science ®Google Scholar
• Kola B, Hubina E, Tucci SA, Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 2005;280:25196-201
   PubMed Web of Science ®Google Scholar
• Kola B, Farkas I, Christ-Crain M, The orexigenic effect of ghrelin is mediated through central activation of the endogenous endocannabinoid system. PLoS One 2008;12:e1797
   Google Scholar
• Matias I, Gonthier MP, Orlando P, Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 2006;91:3171-80
   PubMed Web of Science ®Google Scholar
• Buettner C, Muse ED, Cheng A, Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat Med 2008;14:667-75
   PubMed Web of Science ®Google Scholar
• Di Marzo V, Goparaju SK, Wang L, Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001;410:822-5
   PubMed Web of Science ®Google Scholar
• Annuzzi G, Piscitelli F, Di Marino L, Differential alterations of the concentrations of endocannabinoids and related lipids in the subcutaneous adipose tissue of obese diabetic patients. Lipids Health Dis 2010; published online 28 April 2010; doi:10.1186/1476-511X-9-43
   PubMed Web of Science ®Google Scholar
• Karaloita S, Siafaka-Kapadai A, Gontinou C, Anandamide increases the differentiation of rat adipocytes and causes PPARgamma and CB1 receptor upregulation. Obesity 2009;17:1830-8
   PubMed Web of Science ®Google Scholar
• Yan ZC, Liu DY, Zhang LL, Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta. Biochem Biophys Res Commun 2007;354:427-33
   PubMed Web of Science ®Google Scholar
• Vettor R, Pagano C. The role of the endocannabinoid system in lipogenesis and fatty acid metabolism. Best Pract Res Clin Endocrinol Metab 2009;23:51-63
   PubMed Web of Science ®Google Scholar
• Bensaid M, Gary-Bobo M, Esclangon A, The cannabinoid receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 2003;63:908-14
   PubMed Web of Science ®Google Scholar
• Bermudez-Silva FJ, Suarez J, Baixeras E, Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia 2008;51:476-87
   PubMed Web of Science ®Google Scholar
• Nakata M, Yada T. Cannabinoids inhibit insulin secretion and cytosolic Ca2+ oscillation in islet beta-cells via CB1 receptors. Regul Pept 2008;145:49-53
   PubMed Web of Science ®Google Scholar
• Kim W, Doyle ME, Liu Z, Cannabinoids inhibit insulin receptor signaling in pancreatic beta-cells. Diabetes 2011;60:1198-209
   PubMed Web of Science ®Google Scholar
• Cavuoto P, McAinch AJ, Hatzinikolas G, Effects of cannabinoid receptors on skeletal muscle oxidative pathways. Mol Cell Endocrinol 2007;267:63-9
   PubMed Web of Science ®Google Scholar
• Esposito I, Proto MC, Gazzerro P, The cannabinoid CB1 receptor antagonist rimonabant stimulates 2-deoxyglucose uptake in skeletal muscle cells by regulating the expression of phosphatidylinositol-3-kinase. Mol Pharmacol 2008;74:1678-86
   PubMed Web of Science ®Google Scholar
• Eckhardt K, Sell H, Taube A, Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle. Diabetologia 2009;52:664-74
   PubMed Web of Science ®Google Scholar
• Ameloot K, Jansssen P, Scarpellini E, Endocananbinoid control of gastric sensorimotor function in man. Aliment Pharmacol Ther 2010;31:1123-31
   PubMed Web of Science ®Google Scholar
• Burdyga G, Varro A, Dimaline R, Ghrelin receptors in rat and human nodose ganglia: putative role in regulating CB-1 and MCH receptor abundance. Am J Physiol Gastrointest Liver Physiol 2006;290:G1289-97
   PubMed Web of Science ®Google Scholar
• Roux J, Wanaverbecq N, Jean A, Depolarization-induced release of endocannabinoids by murine dorsal motor nucleus of the vagus nerve neurons differentially regulates inhibitory and excitatory neurotransmission. Neuropharmacology 2009;56:1106-15
   PubMed Web of Science ®Google Scholar
• Osei-Hyiaman D, DePetrillo M, Pacher P, Endocannabinoid activation at hepatic CB1R receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005;115:1298-305
   PubMed Web of Science ®Google Scholar
• Soria-Gοmez E, Guzman K, Pech-Rueda O, Oleoylethanolamide affects food intake and sleep-waking cycle through a hypothalamic modulation. Pharmacol Res 2010;61:379-84
   Google Scholar
• Cluny NL, Keenan CM, Lutz B, The identification of peroxisome proliferator-activated receptor-alpha-independent effects of oleoylethanolamide on intestinal transit in mice. Neurogastroenterol Motil 2009;21:420-9
   PubMed Web of Science ®Google Scholar
• Riedel G, Fadda P, McKillop-Smith S, Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br J Pharmacol 2009;156:1154-66
   PubMed Web of Science ®Google Scholar
• Dodd GT, Mancini G, Lutz B, The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice. J Neurosci 2010;30:7369-76
   PubMed Web of Science ®Google Scholar
• Richard D, Guesdon B, Timofeeva E. The brain endocannabinoid system in the regulation of energy balance. Best Pract Res Clin Endocrinol Metab 2009;23:17-32
   PubMed Web of Science ®Google Scholar
• Onaivi ES. Cannabinoid receptors in brain: pharmacogenetics, neuropharmacology, neurotoxicology, and potential therapeutic applications. Int Rev Neurobiol 2009;88:335-69
   PubMed Web of Science ®Google Scholar
• Cota D, Tschop MH, Horvath TL, Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Rev 2006;51:85-107
   PubMed Web of Science ®Google Scholar
• Di Marzo V, Ligresti A, Cristino L. The endocannabinoid system as a link between homeostatic and hedonic pathways involved in energy balance regulation. Int J Obes 2009;33:S18-24
   Web of Science ®Google Scholar
• D'Eon TM, Pierce KA, Roix JJ, The role of adipocyte insulin reistance in the pathogenesis of obesity-related elevations in endocannabinoids. Diabetes 2008;57:1262-8
   PubMed Web of Science ®Google Scholar
• Bermudez-Silva F, Serrano A, Diaz-Molina FJ, Activation of cannabinoid CB1 receptors induces glucose intolerance in rats. Eur J Pharmacol 2006;531:282-4
   PubMed Web of Science ®Google Scholar
• Ravinet Trillou C, Delgorge C, Menet C, CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord 2004;28:640-8
   PubMed Web of Science ®Google Scholar
• Osei-Hyiaman D, Liu J, Zhou L, Hepatic CB1R receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 2008;118:3160-9
   PubMed Web of Science ®Google Scholar
• Izzo AA, Piscitelli F, Capasso R, Peripheral endocannabinoid dysregulation in obesity: relation to intestinal motility and energy processing induced by food deprivation and re-feeding. Br J Pharmacol 2009;158:451-61
   PubMed Web of Science ®Google Scholar
• Starowicz KM, Cristino L, Matias I, Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with a high-fat diet. Obesity 2008;16:553-65
   PubMed Web of Science ®Google Scholar
• Massa F, Mancini G, Schmidt H, Alterations in the hippocampal endocannabinoid system in diet-induced obese mice. J Neurosci 2010;30:6273-81
   PubMed Web of Science ®Google Scholar
• Guijarro A, Osei-Hyiaman D, Harvey-White J, Sustained weight loss after Roux-en-Y gastric bypass is characterized by down regulation of endocannabinoids and mitochondrial function. Ann Surg 2008;247:779-90
   PubMed Web of Science ®Google Scholar
• Tourino C, Oveisi F, Lockney J, FAAH deficiency promotes energy storage and enhances the motivation for food. Int J Obes 2010;34:557-68
   Web of Science ®Google Scholar
• Lofgren P, Sjolin E, Wahlen K, Hoffstedt J. Human adipose tissue cannabinoid receptor 1 gene expression is not related to fat cell function or adiponectin level. J Clin Endocrinol Metab 2007;92:1555-9
   PubMed Web of Science ®Google Scholar
• Engeli S. Dysregulation of the endocannabinoid system in obesity. J Neuroendocrinol 2008;20:S110-15
   PubMed Web of Science ®Google Scholar
• Engeli S, Bohnke J, Feldpausch M, Activation of the peripheral endocannabinoid system in human obesity. Diabetes 2005;54:2838-43
   PubMed Web of Science ®Google Scholar
• Bluher M, Engeli S, Kloting N, Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 2006;55:3053-60
   PubMed Web of Science ®Google Scholar
• Jumpertz R, Guijarro A, Pratley RE, Central and peripheral endocannabinoids and cognate acylethanolamides in humans: association with race, adiposity, and energy expenditure. J Clin Endocrinol Metab 2011;96:787-91
   PubMed Web of Science ®Google Scholar
• Murdolo G, Kempf K, Hammarstedt A, Insulin differentially modulates the peripheral endocannabinoid system in human subcutaneous abdominal adipose tissue from lean and obese individuals. J Endocrinol Invest 2007;30:RC17-21
   PubMed Web of Science ®Google Scholar
• Cote M, Matias I, Lemieux I, Circulating endocananbinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes 2007;31:692-9
   PubMed Web of Science ®Google Scholar
• Quercioli A, Pataky Z, Vincenti G, Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur Heart J 2011;32:1369-78
   PubMed Web of Science ®Google Scholar
• Kempf K, Hector J, Strate T, Immune-mediated activation of the endocannabinoid system in visceral adipose tissue in obesity. Horm Metab Res 2007;39:596-600
   PubMed Web of Science ®Google Scholar
• Matias I, Gonthiner MP, Orlando P, Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 2006;91:3171-80
   PubMed Web of Science ®Google Scholar
• Bennetzen MF, Wellner N, Ahmed SS, Investigations of the human endocannabinoid system in two subcutaneous adipose tissue depots in lean subjects and in obese subjects before and after weight loss. Int J Obes 2011; published online 15 February 2011; doi:10.1038/ijo.2011.8
   Web of Science ®Google Scholar
• Bennetzen MF. Investigations of the endocannabinoid system in adipose tissue: effects of obesity/weight loss and treatment options. Dan Med Bull 2011;58:B4269
   Google Scholar
• Bennetzen MF, Nielsen TS, Paulsen SK, Reduced cannabinoid receptor 1 protein in subcutaneous adipose tissue of obese. Eur J Clin Invest 2010;40:121-6
   PubMed Web of Science ®Google Scholar
• Strowski MZ, Sparma G, Weber H, Caerulein pancreatitis increases mRNA but reduces protein levels of rat pancreatic heat shock proteins. Am J Physiol 1997;273:G397-45
   Google Scholar
• Greenbaum D, Colangelo C, Williams K, Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol 2003; published online 29 August 2003; doi:10.1186/gb-2003-4-9-117
   PubMed Web of Science ®Google Scholar
• Di Marzo V, Cote M, Matias I, Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: association with changes in metabolic risk factors. Diabetologia 2009;52:213-17
   PubMed Web of Science ®Google Scholar
• Rodondi N, Pletcher MJ, Liu K, Marijuana use, body mass index, and cardiovascular risk factors (from the CARDIA study). Am J Cardiol 2006;98:478-84
   PubMed Web of Science ®Google Scholar
• Smit E, Crespo CJ. Dietary intake and nutritional status of US adult marijuana users: results from the Third National Health and Nutrition Examination Survey. Public Health Nutr 2001;4:781-6
   PubMed Web of Science ®Google Scholar
• Mittleman MA, Lewis RA, Maclure M, Triggering myocardial infarction by marijuana. Circulation 2001;103:2805-9
   PubMed Web of Science ®Google Scholar
• Hayatbakhsh MR, O'Callaghan MJ, Mamun AA, Cannabis use and obesity and young adults. Am J Drug Alcohol Abuse 2010;36:350-6
   PubMed Web of Science ®Google Scholar
• Dinu IR, Popa S, Bicu M, The implication of CNR1 gene's polymorphisms in the modulation of endocannabinoid system effects. Rom J Intern Med 2009;47:9-18
   PubMedGoogle Scholar
• de Luis DA, Gonzalez Sagrado M, Aller R, G1359A polymorphism of the cannabinoid receptor gene (CNR1) and insulin resistance in patients with diabetes mellitus type 2. Nutr Hosp 2010;25:34-8
   PubMed Web of Science ®Google Scholar
• de Luis DA, Gonzalez Sagrado M, Aller R, Influence of G1359A polymorphism of the cannabinoid receptor gene on anthropometric parameters and insulin resistance in women with obesity. Metabolism 2011;60:272-6
   PubMed Web of Science ®Google Scholar
• de Miguel-Yanes JM, Manning AK, Shrader P, Variants at the endocananbinoid receptor CB1 gene (CNR1) and insulin sensitivity, type 2 diabetes, and coronary heart disease. Obesity 2011; published online 2 June 2011; doi:10.1038/oby.2011.135
   PubMed Web of Science ®Google Scholar
• Bordicchia M, Battistoni I, Mancinelli L, Cannabinoid CB1 receptor expression in relation to visceral adipose depots, endocannabinoid levels, microvascular damage, and the presence of the Cnr1 A3813G variant in humans. Metabolism 2010;59:734-41
   PubMed Web of Science ®Google Scholar
• Frost M, Nielsen T, Wraae K, Polymorphisms in the endocannabinoid-receptor 1 in relation to fat mass distribution. Eur J Endocrinol 2010;163:407-12
   PubMed Web of Science ®Google Scholar
• Sipe JC, Scott TM, Murray S, Biomarkers of endocannabinoid system activation in severe obesity. PLoS One 2010; published online 20 January 2010; doi:10.1371/journal.pone.0008792
   PubMed Web of Science ®Google Scholar
• Harismendy O, Bansal V, Bhatia G, Population sequencing of two endocannabinoid metabolic genes identifies rare and common regulatory variants associated with extreme obesity and metabolite level. Genome Biol 2010; published online 30 November 2010; doi:10.1186/gb-2010-11-11-r118
   PubMed Web of Science ®Google Scholar
• Aberle J, Flitsch J, Beck NA, Genetic variation may influence obesity only under conditions of diet: analysis of three candidate genes. Mol Genet Metab 2008;95:188-91
   PubMed Web of Science ®Google Scholar
• Kinzer-Ursem TL, Linderman JJ. Both ligand- and cell-specific parameters control ligand agonism in a kinetic model of G protein-coupled receptor signaling. PLoS Comput Biol 2007; published online 12 January 2007; doi:10.1371/journal.pcbi.0030006
   PubMed Web of Science ®Google Scholar
• Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature 2009;459:356-63
   PubMed Web of Science ®Google Scholar
• Giraldo J. How inverse can a neutral antagonist be? Strategic questions after the rimonabnt issue. Drug Discov Today 2010;15:411-15
   PubMed Web of Science ®Google Scholar
• Aloyo VJ, Berg KA, Clarke WP, Inverse agonism at serotonin and cannabinoid receptors. Prog Mol Biol Transl Sci 2010;91:1-40
   Google Scholar
• Greasley PJ, Clapham JC. Inverse agonism or neutral antagonist at G-protein coupled receptors: a medicinal chemistry challenge worth pursuing? Eur J Pharmacol 2006;553:1-9
   PubMed Web of Science ®Google Scholar
• Bond RA, Ijzerman AP. Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery. Trends Pharmacol Sci 2006;27:92-6
   PubMed Web of Science ®Google Scholar
• Fuxe K, Marcellino D, Borroto-Escuela DO, The changing world of G protein-coupled receptors: from monomers to dimers and receptor mosaics with allosteric receptor-receptor interactions. J Recept Signal Transduct Res 2010;30:272-83
   PubMed Web of Science ®Google Scholar
• Canals M, Milligan G. Constitutive activity of the cannabinoid CB1 receptor regulates the function of co-expressed Mu opiod receptors. J Biol Chem 2008;283:11424-34
   PubMed Web of Science ®Google Scholar
• Gullapalli S, Amrutkar D, Gupta S, Characterization of active and inactive states of CB1 receptor and the differential binding state modulation by cannabinoid agonists, antagonists, and inverse agonists. Neuropharmacology 2010;58:1215-19
   PubMed Web of Science ®Google Scholar
• Scott CW, Peters MF. Label-free whole-cell assays: expanding the scope of GPCR screening. Drug Discov Today 2010;15:704-16
   PubMed Web of Science ®Google Scholar
• Leterrier C, Laine J, Darmon M, Constitutive activation drives compartment-selective endocytosis and axonal targeting of type 1 cannabinoid receptors. J Neurosci 2006;26:3141-53
   PubMed Web of Science ®Google Scholar
• Gifford AN, Samiian L, Gatley SJ, Examination of the effect of the cannabinoid receptor antagonist, CP 55,940, on electrically evoked transmitter release from rat brain slices. Eur J Pharmacol 1997;324:187-92
   PubMed Web of Science ®Google Scholar
• Pan X, Ikeda SR, Lewis DL. SR 141716A acts as an inverse agonist to increase neuronal voltage-dependent Ca2+ currents by reversal of tonic CB1 cannabinoid receptor activity. Mol Pharmacol 1998;54:1064-72
   PubMed Web of Science ®Google Scholar
• McDonald NA, Henstridge CM, Connolly CN, An essential role for constitutive endocytosis, but not activity, in the axonal targeting of the CB1 cannabinoid receptor. Mol Pharmacol 2007;71:976-84
   PubMed Web of Science ®Google Scholar
• Turu G, Simon A, Gyombolai P, The role of diacylglycerol lipase in constitutive and angiotensin AT1 receptor-stimulated cannabinoid CB1 receptor activity. J Biol Chem 2007;282:7753-7
   PubMed Web of Science ®Google Scholar
• Neu A, Foldy C, Soltesz I. Postsynaptic origin of CB1-dependent tonic inhibition of GABA release at cholecystokinin-positive basket cell to pyramidal cell synapses in the CA1 region of the rat hippocampus. J Physiol 2007;578:223-47
   Google Scholar
• Hentges ST, Low MJ, Williams JT. Differential regulation of synaptic inputs by constitutively released endocannabionoids and exogenous cannabinoids. J Neurosci 2005;25:9746-51
   PubMed Web of Science ®Google Scholar
• Daigle TL, Kearn CS, Mackie K. Rapid CB1 cannabinoid receptor desensitization defines the time course of ERK1/2 MAP kinase signaling. Neuropharmacology 2008;54:36-44
   PubMed Web of Science ®Google Scholar
• Navarro G, Ferre S, Cordomi A, Interactions between intracellular domains as key determinants of the quarternary structure and function of receptor heteromers. J Biol Chem 2010;285:27346-59
   PubMed Web of Science ®Google Scholar
• Singh SN, Bakshi K, Mercier RW, Binding between a distal C-terminus fragment of cannabinoid receptor 1 and arrestin-2. Biochemistry 2011;50:2223-34
   PubMed Web of Science ®Google Scholar
• Gomez O, Arevalo-Martin A, Garcia-Ovejero D, The constitutive production of the endocannabinoid 2-arachidonoylglycerol participates in oligodendrocyte differentiation. Glia 2010;58:1913-27
   PubMed Web of Science ®Google Scholar
• Casarosa P, Kiechle T, Bakker RA. Differential inverse agonism at the human muscarinic M3 receptor. Methods Enzymol 2010;485:81-101
   PubMed Web of Science ®Google Scholar
• Sirohi S, Dighe SV, Madia PA, The relative potency of inverse opioid agonists and a neutral opioid antagonist in precipitated withdrawal and antagonism of analgesia and toxicity. J Pharmacol Exp Ther 2009;330:513-19
   PubMed Web of Science ®Google Scholar
• Thornton-Jones ZD, Kennett GA, Benwell KR, The cannabinoid CB1 receptor inverse agonist, rimonabant, modifies body weight and adiponectin function in diet-induced obese rats as a consequence of reduced food intake. Pharmacol Biochem Behav 2006;84:353-9
   PubMed Web of Science ®Google Scholar
• Richey JM, Woolcott OO, Stefanovski D, Rimonabant prevents additional accumulation of visceral and subcutaneous fat during high-fat feeding in dogs. Am J Physiol Endocrinol Metab 2009;296:E1311-18
   PubMed Web of Science ®Google Scholar
• Getty-Kaushik L, Richard AM, Deeney JT, The CB1 antagonist rimonabant decreases insulin hypersecretion in rat pancreatic islets. Obesity 2009;17:1856-60
   PubMed Web of Science ®Google Scholar
• Griffith DA, Hadcock JR, Black SC, Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperidine-4-carboxylic acid amide hydrochloride (CP945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist. J Med Chem 2009;52:234-7
   PubMed Web of Science ®Google Scholar
• Hadcock JR, Carpino PA, Iredale PA, Quantitative in vitro and in vivo pharmacological profile of CE-178253, a potent and selective cannabinoid type 1 (CB1) receptor antagonist. BMC Pharmacol 2010. Available from: http://www.biomedcentral.com/1471-2210/10/9 [Last accessed 21 July 2011]
   Google Scholar
• Wagner JD, Zhang L, Kavanagh K, A selective cannabinoid-1 receptor antagonist, PF-95453, reduces body weight and body fat to a greater extent than pair-fed controls in obese monkeys. J Pharmacol Exp Ther 2010;335:103-13
   PubMed Web of Science ®Google Scholar
• Chen W, Tang H, Liu H, Novel selective antagonist of the cannabinoid CB1 receptor, MJ15, with prominent anti-obesity effect in rodent models. Eur J Pharmacol 2010;637:178-85
   PubMed Web of Science ®Google Scholar
• Jourdan T, Djaouti L, Demizieux L, CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice. Diabetes 2010;59:926-34
   PubMed Web of Science ®Google Scholar
• Wang Q, Perrard XD, Perrard JL, Effect of the cannabinoid receptor-1 antagonist rimonabnt on inflammation in mice with diet-induced obesity. Obesity 2011;19:505-13
   PubMed Web of Science ®Google Scholar
• Crespillo A, Suarez J, Bermudez-Silva FJ, Expression of cannabinoid system in muscle: effects of high fat diet and CB1 receptor blockade. Biochem J 2010;433:175-85
   Web of Science ®Google Scholar
• Despres JP. The endocannabinoid system: a new target for the regulation of energy balance and metabolism. Crit Pathw Cardiol 2007;6:46-50
   PubMedGoogle Scholar
• Mølhøj S, Hansen HS, Schweiger M, Effect of the cannabinoid receptor-1 antagonist rimonabant on lipolysis in rats. Eur J Pharmacol 2010;646:38-45
   PubMed Web of Science ®Google Scholar
• Lazzari P, Sanna A, Mastinu A, Weight loss induced by rimonabant is associated with an altered leptin expression and hypothalamic leptin signaling in diet-induced obese mice. Behav Brain Res 2011;217:432-8
   PubMed Web of Science ®Google Scholar
• Janiak P, Poirier B, Bidouard JP, Blockade of cannabinoid CB1 receptors improves renal function, metabolic profile, and increased survival of obese Zucker rats. Kidney Int 2007;72:1345-57
   PubMed Web of Science ®Google Scholar
• Herlig AW, Kilp S, Elvert R, Increased energy expenditure contributes more to the body weight-reducing effect of rimonabant than reduced food intake in candy-fed Wistar rats. Endocrinology 2008;149:2557-66
   PubMed Web of Science ®Google Scholar
• Scheen AJ, Paquot N. Inhibitors of cannabinoid receptors and glucose metabolism. Curr Opin Clin Nutr Metab Care 2008;11:505-11
   PubMed Web of Science ®Google Scholar
• Cota D, Sandoval DA, Olivieri M, Food intake-independent effects of CB1 antagonism on glucose and lipid metabolism. Obesity 2009;17:1641-5
   PubMed Web of Science ®Google Scholar
• DiPatrizio NV, Simansky KJ. Activating parabrachial cananbinoid CB1 receptors selectively stimulates feeding of palatable foods in rats. J Neurosci 2008;28:9702-9
   PubMed Web of Science ®Google Scholar
• Nogueiras R, Veyrat-Durebex C, Suchanek PM, Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats. Diabetes 2008;57:2997-1
   Google Scholar
• Gomez R, Navarro M, Ferrer B, A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 2002;22:9612-17
   PubMed Web of Science ®Google Scholar
• Son M-H, Kim HD, Chae YN, Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control. Int J Obes 2010;34:547-56
   PubMed Web of Science ®Google Scholar
• Zhao W, Fong O, Muise ES, Genome-wide expression profiling revealed peripheral effects of cananbinoid receptor 1 inverse agonists in improving insulin sensitivity and metabolic parameters. Mol Pharmacol 2010;78:350-9
   PubMed Web of Science ®Google Scholar
• O'Hare JD, Zielinski E, Cheng B, Central endocannabinoid signaling regulates hepatic glucose production and systemic lipolysis. Diabetes 2011;60:1055-62
   PubMed Web of Science ®Google Scholar
• Lee HK, Choi EB, Pak CS. The current status and future perspectives of studies of cannabinoid receptor 1 antagonists as anti-obesity agents. Curr Top Med Chem 2009;9:482-503
   PubMed Web of Science ®Google Scholar
• Ligresti A, Petrosino S, Di Marzo V. From endocannabinoid profiling to ‘endocannabinoid therapeutics’. Curr Opin Chem Biol 2009;13:321-31
   PubMed Web of Science ®Google Scholar
• Scheen AJ. CB1 receptor blockade and its impact on cardiometabolic risk factors: overview of the RIO programme with rimonabant. J Neuroendocrinol 2008;20(Suppl 1):139-46
   PubMedGoogle Scholar
• Van Gaal LF, Rissanen AM, Scheen AJ, Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005;365:1389-97
   PubMed Web of Science ®Google Scholar
• Despres JP, Golay A, Sjostrom L, Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353:2121-34
   PubMed Web of Science ®Google Scholar
• Pi-Sunyer FX, Aronne LJ, Heshmati HM, Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 2006;295:761-75
   PubMed Web of Science ®Google Scholar
• Scheen AJ, Finer N, Hollander P, RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006;368:1660-72
   PubMed Web of Science ®Google Scholar
• Kintscher U. The cardiometabolic drug rimonabant: after 2 years of RIO-Europe and Stradivarius. Eur Heart J 2008;29:1709-10
   PubMed Web of Science ®Google Scholar
• Rosenstock J, Hollander P, Chevalier S, SERENADE: the study evaluating rimonabant efficiacy in drug-naive diabetic patients: effects of monotherapy with rimonabant, the first selective CB1 receptor antagonist, on glycemic control, body weight and lipid profile in drug-naive type 2 diabetes. Diabetes Care 2008;31:2169-76
   PubMed Web of Science ®Google Scholar
• Van Gaal LF, Scheen AJ, Rissanen AM, Long-term effect of CB1 blockade with rimonabant on cardiometaobic risk factors: two year results from the RIO-Europe study. Eur Heart J 2008;29:1761-71
   PubMed Web of Science ®Google Scholar
• Van Gaal L, Pi-Sunyer X, Despres JP, Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the Rimonabant in Obesity (RIO) program. Diabetes Care 2008;31:S229-40
   PubMed Web of Science ®Google Scholar
• Ruilope LM, Despres JP, Scheen A, Effect of rimonabant on blood pressure in overweight/obese patients with/without co-morbidities: analysis of pooled RIO study results. J Hypertens 2008;26:357-67
   PubMed Web of Science ®Google Scholar
• Despres JP, Ross R, Boka G, Effect of rimonabant on the high-triglyceride/low-LDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: the ADAGIO-Lipids trial. Atheroscler Thromb Vasc Biol 2009;29:416-23
   PubMed Web of Science ®Google Scholar
• Hollander PA, Amod A, Litwak LE, Effect of rimonabant on glycemic control in insulin-treated type 2 diabetics: the ARPEGGIO trial. Diabetes Care 2010;33:605-7
   PubMed Web of Science ®Google Scholar
• Di Marzo V, Despres J-P. CB1 antagonists for obesity– what lessons have we learned from rimonabant? Nat Rev Endocrinol 2009;5:633-8
   PubMed Web of Science ®Google Scholar
• Pan C, Yoo HJ, Ho L-T. Perspectives of CB1 antagonist in treatment of obesity: experience of RIO-Asia. J Obes 2010; Published online 29 December 2010; doi:10.1155/2011/957268
   PubMedGoogle Scholar
• Christopoulou FD, Kiortsis DN. An overview of the metabolic effects of rimonabant in randomized controlled trials: potential for other cannabinoid 1 receptor blockers in obesity. J Clin Pharm Ther 2011;36:10-18
   PubMed Web of Science ®Google Scholar
• Nissen SE, Nicholls SJ, Wolski K, Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 2008;299:1547-60
   PubMed Web of Science ®Google Scholar
• Topol EJ, Bousser M-G, Fox KAA, Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 2010;376:517-23
   PubMed Web of Science ®Google Scholar
• O'Leary DH, Reuwer AQ, Nisses SN, Effect of rimonmabant on carotid intima-media thickness (CIMT) progression in patients with abdominal obesity and metaboic syndrome: the AUDITOR trial. Heart 2011;97:1143-50
   PubMed Web of Science ®Google Scholar
• DeSouza CM, Legedza ATR, Sankoh AJ. An overview of practical approaches for handling missing data in clinical trials. J Biopharm Stat 2009;19:1055-73
   PubMed Web of Science ®Google Scholar
• Tonstad S. Is rimonabant a safe and effective therapy for sustained weight loss and improved cardiometabolic risk factors? Commentary. Nat Clin Pract Cardiovasc Med 2006;3:364-5
   PubMedGoogle Scholar
• Proietto J, Rissanen A, Harp JB, A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study. Int J Obes 2010;34:1243-54
   Web of Science ®Google Scholar
• Addy C, Wright H, Van Laere K, The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab 2008;7:68-78
   PubMed Web of Science ®Google Scholar
• Aronne LJ, Tonstad S, Moreno M, A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study. Int J Obes 2010;34:919-35
   Web of Science ®Google Scholar
• Kipnes MS, Hollander P, Fujioka K, A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes. Diabetes Obes Metab 2010;12:517-31
   PubMed Web of Science ®Google Scholar
• Wadden TA, Fujioka K, Toubro S, A randomized trial of lifestyle modification and taranabant for maintaining weight loss achieved with a low-calorie diet. Obesity 2010;18:2301-10
   PubMed Web of Science ®Google Scholar
• Amundsen MO, Engdahl B, Berg C, Nordeng H. Use of psychotropic drugs and analgesics among users of antiobesity drugs– a population based study. Pharmacoepidemiol Drug Saf 2010;19:273-9
   PubMed Web of Science ®Google Scholar
• Marco EM, Viveros MP. The critical role of the endocannabinoid system in emotional homeostasis: avoiding excess and deficiencies. Mini Rev Med Chem 2009;9:1407-15
   PubMed Web of Science ®Google Scholar
• Taber KH, Hurley RA. Endocannabinoids: stress, anxiety, and fear. J Neuropsychiatry Clin Neurosci 2009;21:109-13
   Google Scholar
• Sidhpura N, Parsons LH. Endocannabinoid-mediated synaptic plasticity and addiction-related behavior. Neuropharmacology 2011; published online 29 May 2011; doi:10.1016/j.neuropharm.2011.05.034
   PubMed Web of Science ®Google Scholar
• Steiner MA, Marsciano G, Wotjak CT, Conditioned cannabinoid receptor type 1 mutants reveal neuron subpopulation-specific effects on behavioral and neuroendocrine stress responses. Psychoneuroendocrinology 2008;33:1165-70
   PubMed Web of Science ®Google Scholar
• Mikics E, Vas J, Aliczki M, Interactions between the anxiogenic effects of CB1 gene disruption and 5-HT3 neurotransmission. Behav Pharmacol 2009;20:265-72
   PubMed Web of Science ®Google Scholar
• Martin M, Ledent C, Parmentier M, Involvement of CB1 cannabinoid receptors in emotional behavior. Psychopharmacology (Berl) 2002;159:379-87
   PubMed Web of Science ®Google Scholar
• Mackie K. Understanding cannabinoid psychoactivity with mouse genetic models. PLoS Biol 2007; published online 9 October 2007; doi:10.1371/journal.pbio.0050280
   PubMed Web of Science ®Google Scholar
• Thiemann G, Watt CA, Ledent C, Modulation of anxiety by acute blockade and genetic deletion of the CB(1) cannabinoid receptor in mice together with biogenic amine changes in the forebrain. Behav Brain Res 2009;200:60-7
   PubMed Web of Science ®Google Scholar
• Haller J, Varga B, Ledent C, Context-dependent effects of CB1 cannabinoid gene disruption on anxiety-like and social behavior in mice. Eur J Neurosci 2004;19:1906-12
   PubMed Web of Science ®Google Scholar
• Rodgers RJ, Evans PM, Murphy A. Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naive and plus-maze-experienced mice. Behav Pharmacol 2005;16:405-13
   PubMed Web of Science ®Google Scholar
• Griebel G, Stemmelin J, Scatton B. Effects of the cannabinoid CB1 receptor antagonist rimonabant in models of emotional reactivity in rodents. Biol Psychiatry 2005;57:261-7
   PubMed Web of Science ®Google Scholar
• Beyer CE, Dwyer JM, Piesla MJ, Depression-like phenotype following chronic CB1 receptor antagonism. Neurobiol Dis 2010;39:148-55
   PubMed Web of Science ®Google Scholar
• Sink KS, Segovia KN, Collins LE, The CB1 inverse agonist AM251, but not the CB1 antagonist AM4113, enhances retention of contextual fear conditioning in rats. Physiol Biochem Behav 2010;95:479-84
   PubMed Web of Science ®Google Scholar
• Sink KS, Segovia KN, Sink J, Potential anxiogenic effects of cannabinoid CB1 receptor antagonists/inverse agonists in rats: comparisons between AM4113, AM251, and the benzodiazepine inverse agonist FG-7142. Eur Neuropsychopharmacol 2010;20:112-22
   PubMed Web of Science ®Google Scholar
• Moriera FA, Grieb M, Lutz B. Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best Pract Res Clin Endocrinol Metab 2009;23:133-44
   PubMed Web of Science ®Google Scholar
• Haller J, Varga B, Ledent C, CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents. Behav Pharmacol 2004;15:299-304
   PubMed Web of Science ®Google Scholar
• Lee S, Kim DH, Yoon S-H, Ryu JH. Sub-chronic administration of rimonabant causes loss of antidepressive activity and decreases doublecortin immunoreactivity in the mouse hippocampus. Neurosci Lett 2009;467:111-16
   PubMed Web of Science ®Google Scholar
• Juhasz G, Chase D, Pegg E, CN1R gene is associated with high neuroticism and low agreeableness and interacts with recent negative life events to predict current depressive symptoms. Neuropsychopharmacology 2009;34:2019-27
   PubMed Web of Science ®Google Scholar
• Bhattacharyya S, Morrison PD, Fusar-Poli P, Opposite effects of delta9-tetraydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 2010;35:764-74
   PubMed Web of Science ®Google Scholar
• Karschner EL, Darwin WD, McMahon RP, Subjective and physiological effects after controlled Sativex and oral THC adminstration. Clin Pharmacol Ther 2011;89:400-7
   PubMed Web of Science ®Google Scholar
• Horder J, Browning M, Di Simplicio M, Effects of 7 days of treatment with the cannabinoid type 1 receptor antagonist, rimonabant, on emotional processing. J Psychopharmacol 2011; published online 15 March 2011; doi:10.1177/0269881111400649
   Web of Science ®Google Scholar
• Christensen R, Kristensen PK, Bartels EM, Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007;370:1706-13
   PubMed Web of Science ®Google Scholar
• Fabricatore AN, Wadden TA, Moore RH, Attrition from randomized controlled trials of pharmacological weight loss agents: a systematic review and analysis. Obes Rev 2009;10:333-41
   PubMed Web of Science ®Google Scholar
• Shelton RC, Miller AH. Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. Prog Neurobiol 2010;91:275-99
   PubMed Web of Science ®Google Scholar
• Luppino FS, de Wit LM, Bouvy PF, Overweight, obesity, and depression. A systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry 2010;67:220-9
   PubMed Web of Science ®Google Scholar
• Gariepy G, Nitka D, Schmitz N. The association between obesity and anxiety disorders in the population: a systematic review and meta-analysis. Int J Obes 2010;34:407-19
   PubMed Web of Science ®Google Scholar
• Rumsfeld JS, Nallamothu BK. The hope and fear of rimonabant. JAMA 2008;299:1601-2
   PubMed Web of Science ®Google Scholar
• Addy C, Li S, Agrawal N, Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity: results from a double-blind, placebo-controlled, single oral dose study in healthy volunteers. J Clin Pharmacol 2008;48:418-27
   PubMed Web of Science ®Google Scholar
• Morrison MF, Ceesay P, Gantz I, Randomized, controlled, double-blind trial of taranabant for smoking cessation. Psychopharmacology (Berl) 2010;209:245-53
   PubMed Web of Science ®Google Scholar
• Fulmer T. Not cutting the fat. Bio Century 2008;16:A9-A10
   Google Scholar
• Martin EI, Ressler KJ, Binder E, The neurobiology of anxiety disorders; brain imaging, genetics, and psychoneuroendocrinology. Clin Lab Med 2010;30:865-91
   PubMed Web of Science ®Google Scholar
• Lee S, Jeong J, Kwak Y, Depression research: where are we now? Mol Brain 2010; published online 10 March 2010; doi:10.1186/1756-6606-3-8
   Google Scholar
• Holzel L, Harter M, Reese C, Risk factors for chronic depression – a systematic review. J Affect Disord 2011;129:1-13
   PubMed Web of Science ®Google Scholar
• Faith MS, Butryn M, Wadden TA, Evidence for prospective associations among depression and obesity in population-based studies. Obes Rev 2011; published online 17 March 2011; doi:10.1111/j.1467-789X.2010.00843.x
   PubMed Web of Science ®Google Scholar
• Chaput J-P, Tremblay A. Well-being of obese individuals; therapeutic perspectives. Future Med Chem 2010;2:1729-33
   PubMed Web of Science ®Google Scholar
• Fabricatore AN, Wadden TA, Higginbotham AL, Intentional weight loss and changes in symptoms of depression: a systematic review and meta-analysis. Int J Obes 2011; published online 22 February 2011; doi: 10.1038/ijo.2011.2
   Web of Science ®Google Scholar
• Jones D. End of the line for cannabinoid receptor 1 as an anti-obesity target? Nat Rev Drug Discov 2008;7:961-2
   PubMed Web of Science ®Google Scholar
• Rimonabant: marketing authorization suspended…at last: withdrawal. Half measures. Prescrire Int 2009;18:61
   Google Scholar
• Scheen AJ, Paquot N. Use of cannabinoid CB1 receptor antagonists for the treatment of metabolic disorders. Best Pract Res Clin Endocrinol Metab 2009;23:103-16
   PubMed Web of Science ®Google Scholar
• Mach F, Montecucco F, Steffens S. Effect of blockage of the endocannabinoid system by CB(1) antagonism on cardiovascular risk. Pharmacol Rep 2009;61:13-21
   PubMed Web of Science ®Google Scholar
• Ward SJ, Raffa RB. Rimonabant redux and strategies to improve the future outlook of CB1 receptor neutral-antagonist/inverse-agonist therapies. Obesity 2011;19:1325-3
   PubMed Web of Science ®Google Scholar
• Kunos G, Tam J. The case for peripheral CB1 receptor blockade in the treatment of visceral obesity and its cardiometabolic complications. Br J Pharmacol 2011;163:1423-31
   PubMed Web of Science ®Google Scholar
• Wu Y-K, Yeh C-F, Ly TW, A new perspective of cannabinoid 1 receptor antagonists: approaches toward peripheral CB1R blockers without crossing the blood-brain barrier. Curr Top Med Chem 2011;11:1421-9
   PubMed Web of Science ®Google Scholar
• Hitchcock SA. Blood-brain barrier permeability considerations for CNS-targeted compound library design. Curr Opin Chem Biol 2008;12:318-23
   PubMed Web of Science ®Google Scholar
• Potschka H. Targeting the brain– surmounting or bypassing the blood-brain barrier. Handb Exp Pharmacol 2010;197:411-31
   PubMedGoogle Scholar
• Fong TM, Heymsfield SB. Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions. Int J Obes 2009;33:947-55
   PubMed Web of Science ®Google Scholar
• Hurst DP, Lynch DL, Barnett-Norris J, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) interaction with LYS 3.28(192) is crucial for its inverse agonism at the cannabinoid CB1 receptor. Mol Pharmacol 2002;62:1274-87
   PubMed Web of Science ®Google Scholar
• Hurst D, Umejiego U, Lynch D, Biarypyraxole inverse agonists at the cannabinoid CB1 receptor: importance of the C-3 carboxamide oxygen/lysine3.28(192) interaction. J Med Chem 2006;49:5969-87
   PubMed Web of Science ®Google Scholar
• Cooper M, Receveur J-M, Bjurling E, Exploring SAR features in diverse library of 4-cyanomethyl-pyrazole-3-carboxamides suitable for further elaborations as CB1 antagonists. Bioorg Med Chem Lett 2010;20:26-30
   PubMed Web of Science ®Google Scholar
• Hortala L, Rinaldi-Carmona M, Cogny C, Rational design of a novel peripherally-restricted, orally active CB1 cannabinoid antagonist containing a 2,3-diarylpyrrople motif. Bioorg Med Chem Lett 2010;20:4573-7
   PubMed Web of Science ®Google Scholar
• Becker G, Blum HE. Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus. Lancet 2009;373:1198-206
   PubMed Web of Science ®Google Scholar
• Recevuer J-M, Murray A, Linget J-M, Conversion of 4-cyanomethyl-pyrazole-3-carboxamides into CB1 antagonists with lowered propensity to pass the blood-brain-barrier. Bioorg Med Chem Lett 2010;20:453-7
   PubMed Web of Science ®Google Scholar
• Madsen-Duggan CB, Debenham JS, Walsh TF, Dihydro-pyrano[2,3-b]pyridines and tetrahydro-1,8-haphthyridines as CB1 receptor inverse agonists: synthesis, SAR and biological evaluation. Bioorg Med Chem Lett 2010;20:3750-4
   PubMed Web of Science ®Google Scholar
• Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002;42:620-43
   PubMed Web of Science ®Google Scholar
• Debenham JS, Madsen-Duggan C, Toupence RB, Furo[2,3-b]pyridine-based cannabinoid-1 receptor inverse agonists: synthesis and biological evaluation. Part 1. Bioorg Med Chem Lett 2010;20:1448-52
   PubMed Web of Science ®Google Scholar
• Yan L, Huo P, Debenham JS, Discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano-[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. J Med Chem 2010;53:4028-37
   PubMed Web of Science ®Google Scholar
• 7TM Pharma. TM38837. 2010. Available from: http://7tm.com/R-D/Metabolic_Disorders/TM38837.aspx [Last accessed 21 July 2011]
   Google Scholar
• Arrowsmith J. Phase III and submission failures: 2007 – 2010. Nat Rev Drug Discov 2011;10:87
   PubMed Web of Science ®Google Scholar
• Tam J, Vemuri VK, Liu J, Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest 2010;120:2953-66
   PubMed Web of Science ®Google Scholar
• Patti M-E. Rehashing endocannabinoid antagonists: can we selectively target the periphery to safely treat obesity and type 2 diabetes? J Clin Invest 2010;120:2646-8
   PubMed Web of Science ®Google Scholar
• Smit MJ, Vischer HF, Bakker RA, Pharmacogenomic and structural analysis of constitutive G protein-coupled receptor activity. Annu Rev Pharmacol Toxicol 2007;47:53-87
   PubMed Web of Science ®Google Scholar
• Tao YX. Constitutive activation of G protein-coupled receptors and diseases: insights into mechanisms of activation and therapeutics. Pharmacol Ther 2008;120:129-48
   PubMed Web of Science ®Google Scholar
• Thompson MD, Cole DE, Jose PA. Pharmacogenomics of G protein-coupled receptor signaling: insights from health and disease. Methods Mol Biol 2008;448:77-107
   PubMedGoogle Scholar
• Bergman J, Delatte MS, Paronis CA, Some effects of CB1 antagonists with inverse agonist and neutral antagonist biochemical properties. Physiol Biochem Behav 2008;18:666-70
   Google Scholar
• Govaerts SJ, Muccioli GG, Hermans E, Lambert DM. Characterization of the pharmacology of imidazolidinedione derivatives at cannabinoid CB1 and CB2 receptors. Eur J Pharmacol 2004;495:43-53
   PubMed Web of Science ®Google Scholar
• Ruiu S, Pinna GA, Marchese G, Synthesis and characterization of NESS 0327: a novel putative antagonist of the CB1 cannabinoid receptor. J Pharmacol Exp Ther 2003;306:363-70
   PubMed Web of Science ®Google Scholar
• Thomas A, Ross RA, Saha B, 6”-Azidohex-2”-yne-cannabidiol: a potential neutral, competitive cannabinoid CB1 receptor antagonist. Eur J Pharmacol 2004;487:213-21
   PubMed Web of Science ®Google Scholar
• Fride E, Braun H, Matan H, Inhibition of milk ingestion and growth after administration of a neutral acannabinoid CB1 receptor antagonist on the first postnatal day in the mouse. Pediatr Res 2007;62:533-6
   PubMed Web of Science ®Google Scholar
• Bostrom J, Olsson RI, Tholander J, Novel thioamide derivatives as neutral CB1 receptor antagonists. Bioorg Med Chem Lett 2010;20:479-82
   PubMed Web of Science ®Google Scholar
• Bostrom J, Berggren K, Elebring T, Scaffold hopping, synthesis and structure-activity relationships of 5,6-diaryl-pyrazine-2-amide derivatives: a novel series of CB1 receptor antagonists. Bioorg Med Chem 2007;15:4077-84
   PubMed Web of Science ®Google Scholar
• Tseng S-L, Hung M-S, Chang C-P, Biosteric replacement of the pyrazole 5-aryl moiety of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). A novel series of alkynylthiophenes as potent and selective cannabinoid-1 receptor antagonists. J Med Chem 2008;51:5397-412
   PubMed Web of Science ®Google Scholar
• Lin Y, Shia K-S, Hsiao W-C, Biphasic suppression of appetite by cannabinoid CB1 receptor antagonists with distinct functional activities. Pharmacol Res 2010;62:337-43
   PubMed Web of Science ®Google Scholar
• Chambers AP, Vemuri VK, Peng Y, A neutral CB1 receptor receptor antagonist reduces weight gain in rat. Am J Physiol Regul Integr Comp Physiol 2007;293:R2185-93
   PubMed Web of Science ®Google Scholar
• Sink KS, McLaughlin PJ, Wood JA, The novel cannabinoid CB1R receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology 2008;33:946-55
   PubMed Web of Science ®Google Scholar
• Sink KS, Vemuri VK, Wood J, Oral bioavailability of the novel cannabinoid CB1 antagonist AM6527: effects on food-reinforced behavior and comparisons with AM4113. Pharmacol Biochem Behav 2009;91:303-6
   PubMed Web of Science ®Google Scholar
• Cluny NL, Chambers AP, Vemuri VK, The neutral cannabinoid CB(1) receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat. Pharmacol Biochem Behav 2011;97:537-43
   PubMed Web of Science ®Google Scholar
• Salamone JD, McLaughlin PJ, Sink K, Cannabinoid CB1 receptor inverse agonists and neutral anagonists: effects on food intake, food-reinforced behavior and food aversions. Physiol Behav 2007;91:383-8
   PubMed Web of Science ®Google Scholar
• Sink KS, Vemuri VK, Olszewska T, Cannabinoid CB1R antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior. Psychopharmacology 2008;196:565-74
   PubMed Web of Science ®Google Scholar
• Hodge J, Bow JP, Plyler KS, The cannabinoid CB1R receptor inverse agonist AM 251 and antagonist AM 4113 produce similar effects on the behavioral satiety sequence in rats. Behav Brain Res 2008;193:298-305
   PubMed Web of Science ®Google Scholar
• Jarbe TU, LeMay BJ, Olszewska T, Intrinsic effects of AM4113, a putative CB1 receptor selective antagonist, on open-field behaviors in rats. Pharmacol Biochem Behav 2008;91:84-90
   PubMed Web of Science ®Google Scholar
• Parker LA, Mechoulam R, Schlievert C, Effects of cannabinoids on lithium-induced conditioned rejection reactions in a rat model of nausea. Psychopharmacology (Berl) 2003;166:156-62
   PubMed Web of Science ®Google Scholar
• Storr MA, Bashashati M, Hirota C, Differential effects of CB1 neutral antagonists and inverse agonists on gastrointestinal motility in mice. Neurogastroenterol Motil 2010;22:787-97
   PubMedGoogle Scholar
• Limebeer CL, Vemuri VK, Bedard H, Inverse agonism of cannabinoid CB1 receptors potentiates LiCl-induced nausea in the conditioned gaping model in rats. Br J Pharmacol 2010;161:336-49
   PubMed Web of Science ®Google Scholar
• Parker LA, Limebeer CL. Conditioned gaping in rats: a selective measure of nausea. Auton Neurosci 2006;129:36-41
   PubMed Web of Science ®Google Scholar
• Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther 2010;126:21-38
   PubMed Web of Science ®Google Scholar
• Horn CC. Why is the neurobiology of nausea and vomiting so important? Appetite 2008;50:430-4
   PubMed Web of Science ®Google Scholar
• Geoffrey G, Pertwee R. New use of cannabinoid. WO06054057; 2006
   Google Scholar
• Vela-Hernandez JM, Yenes Minguez S. 4-Methyl-4,5-dihydro-1H-pyrazole-3-carboxamide useful as a cannabinoid CB1 neutral antagonist. WO09124950; 2009
   Google Scholar
• Makriyannis A, Vemuri VK. CB1 receptor antagonists and uses thereof. WO08154015; 2008
   Google Scholar
• Greig IR, Ross RA, Pertwee RG. 1,5-Diarylpyrazoles as cannabinoid neutral antagonists useful as therapeutic agents. WO08099139; 2009
   Google Scholar
• Greig IR, Ross RA. 1,5-Diarylpyrazoles and their use as cannabinoid neutral antagonists. WO10020762; 2010
   Google Scholar
• LoVerme J, Duranti A, Tontine A, Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice. Bioorg Med Chem Lett 2009;19:639-43
   PubMed Web of Science ®Google Scholar
• Cluny NL, Vemuri VK, Chambers AP, A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduced food intake and body weight, but does not cause malaise, in rodents. Br J Pharmacol 2010;161:629-42
   PubMed Web of Science ®Google Scholar
• Randall PA, Vemuri VK, Segovia KN, The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior. Pharmacol Biochem Behav 2010;97:179-84
   PubMed Web of Science ®Google Scholar
• Makriyannis A, Vemuri VK, Thotapally R, Olszewska T. Novel heteropyrrole analogs acting on cannabinoid receptors. WO10104488; 2006
   Google Scholar
• Bokoch MP, Zou Y, Rasmussen SG, Ligand-specific recognition of the extracellular surface of a G-protein-coupled receptor. Nature 2010;463:108-12
   PubMed Web of Science ®Google Scholar
• Nie J, Lewis DL. Structural domains of the CB1 cannabinoid receptor that contribute to constitutive activity and G-protein sequestration. J Neurosci 2001;21:8758-64
   PubMed Web of Science ®Google Scholar
• Reggio PH. Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem 2010;17:1468-86
   PubMed Web of Science ®Google Scholar
• Pertwee RG. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 2005;76:1307-24
   PubMed Web of Science ®Google Scholar
• Sim-Selley LJ, Brunk LK, Selley DE. Inhibitory effects of SR141716A on G-protein activation in rat brain. Eur J Pharmacol 2001;414:135-43
   PubMed Web of Science ®Google Scholar
• Sela I, Golan G, Strajbl M, G protein coupled receptors– in silico drug discovery and design. Curr Top Med Chem 2010;10:638-56
   PubMed Web of Science ®Google Scholar
• Hubbard RE. Structure-based drug discovery and protein targets in the CNS. Neuropharmacology 2011;60:7-23
   PubMed Web of Science ®Google Scholar
• Mensch J, Oyarzabal J, Mackie C, Augustijns P. In vivo, in vitro, and in silico methods for small molecule transfer across the BBB. J Pharm Sci 2009;98:4429-68
   PubMed Web of Science ®Google Scholar
• Harrison C, Traynor JR. The [35S]GTPgammaS binding assay: approaches and applications in pharmacology. Life Sci 2003;74:489-508
   PubMed Web of Science ®Google Scholar
• Nelson CP, Challis RAJ. ‘Phenotypic’ pharmacology: the influence of cellular environment on G protein-coupled receptor antagonist and inverse agonist pharmacology. Biochem Pharmacol 2007;73:737-51
   PubMed Web of Science ®Google Scholar
• Pavon FJ, Serrano A, Perez-Valero V, Central versus peripheral antagonism of cannabinoid CB1 receptor in obesity: effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist, in Zucker rats. J Neuroendocrinol 2008;20(Suppl 1):116-23
   PubMed Web of Science ®Google Scholar
• Jagerovic N, Hernandez-Folgado L, Alkorta I, Discovery of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1h-1,2,4-triazole, a novel in vivo cannabinoid antagonist containing a 1,2,4-triazole motif. J Med Chem 2004;47:2939-42
   PubMed Web of Science ®Google Scholar
• Chen RZ, Frassetto A, Lao JZ, Pharmacological evaluation of LH-21, a newly discovered molecule that binds to cannabinoid CB1 receptor. Eur J Pharmacol 2008;584:338-42
   PubMed Web of Science ®Google Scholar
• Pavon FJ, Bilbao A, Hernandez-Folgado L, Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole–LH 21. Neuropharmacology 2006;51:358-66
   PubMed Web of Science ®Google Scholar
• Horswell JG, Bali U, Shaaban S, PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats. Br J Pharmacol 2007;152:805-14
   PubMed Web of Science ®Google Scholar
• Wiley JL, Breivogel CS, Mahadevan A, Structural and pharmacological analysis of O-2015, a putative neutral cannabinoid CB1 receptor antagonist. Eur J Pharmacol 2011;656:63-7
   PubMedGoogle Scholar
• Gardner A, Mallet PE. Suppression of feeding, drinking, and locomotion by a putative cannabinoid receptor ‘silent antagonist’. Eur J Pharmacol 2006;530:103-6
   PubMed Web of Science ®Google Scholar
• Cryan JF, Slattery DA. Animal models of mood disorders: recent developments. Curr Opin Psychiatry 2007;20:1-7
   PubMed Web of Science ®Google Scholar
• Pollak DD, Rey CE, Monje FJ. Rodent models in depression research: classical strategies and new directions. Ann Med 2010;42:252-64
   PubMed Web of Science ®Google Scholar
• Dain A, Repossi G, Das UN, Eynard AR. Role of PUFAs, the precursors or endocannabinoids, in human obesity and type 2 diabetes. Front Biosci 2010;2:1432-47
   Google Scholar
• Herper M. Orexigen rejection kills obesity drug field. Forbes 2011. Available from: http://blogs.forbes.com/matthewherper/2011/02/01 [Last accessed 21 July 2011]
   Google Scholar
• Quercioli A, Pataky Z, Vincenti G, Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur Heart J 2011;32:1369-78
   PubMed Web of Science ®Google Scholar
• Anuurad E, Bremer A, Berglund L. HIV protease inhibitors and obesity. Curr Opin Endocrinol Diabetes Obes 2010;17:478-85
   PubMed Web of Science ®Google Scholar
• Keller J, Layer P. Intestinal and anorectal motility and functional disorders. Best Pract Res Clin Gastroenterol 2009;23:407-23
   PubMed Web of Science ®Google Scholar
• Effect of rimonabant on weight gain and body composition in adults with Prader Willi Syndrome (PWS). 2008. Available from: http://wwwclinicaltrials.gov/ct2/show/NCT00603109 [Last accessed 21 July 2011]
   Google Scholar
• Cohen C, Kodas E, Griebel G. CB1 receptor antagonists for the treatment of nicotine addiction. Pharmacol Biochem Behav 2005;81:387-95
   PubMed Web of Science ®Google Scholar
• Maccioni P, Colombo G, Caral MA. Blockade of the cannabinoid CB1 receptor and alcohol dependence: preclinical evidence and preliminary clinical data. CNS Neurol Disord Drug Targets 2010;9:55-9
   PubMed Web of Science ®Google Scholar
• Gilman SL. Obesity. The biography. Oxford University Press; Oxford: 2010
   Google Scholar
• Mukherjee S. The emperor of all maladies. A biography of cancer. Scribner; New York: 2010
   Google Scholar
• Hurley D. Diabetes rising. How a rare disease became a modern pandemic, and what to do about it. Kaplan Publishing; New York: 2010
   Google Scholar
• Alisi A, Locatelli M, Nobili V. Nonalcoholic fatty liver disease in children. Curr Opin Clin Nutr Metab Care 2010;13:397-402
   PubMed Web of Science ®Google Scholar
• Feber J, Ahmed M. Hypertension in children: new trends and challenges. Clin Sci 2010;119:151-61
   PubMed Web of Science ®Google Scholar
• Jarbe TUC, LeMay BJ, Vemuri VK, Central mediation and differential blockade by cannabinergics of the discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats. Psychopharmacology 2011;216:355-65
   PubMed Web of Science ®Google Scholar
• Lane MD. The biotin connection: Severo Ochoa, Harland Wood, and Feodor Lynen. J Biol Chem 2004;279:39187-94
   PubMed Web of Science ®Google Scholar
• Kresge N, Simoni RD, Hill RL. Acetyl-CoA carboxylase and other biotin-dependent enzymes: the work of M. Daniel Lane. J Biol Chem 2006;281:e40-2
   Google Scholar