Abstract
Aim:
To characterize the biological profiles of MJ08, a novel selective CB1 receptor antagonist.
Methods:
Radioligand binding assays were performed using rat brain and spleen membrane preparations. CB1 and CB2 receptor redistribution and intracellular Ca2+ ([Ca2+]i) assays were performed with IN CELL Analyzer. Inverse agonism was studied using intracellular cAMP assays, and in guinea-pig ileum and mouse vas deferens smooth muscle preparations. In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice.
Results:
In radioligand binding assay, MJ08 selectively antagonized CB1 receptor (IC50=99.9 nmol/L). In EGFP-CB1_U2OS cells, its IC50 value against CB1 receptor activation was 30.23 nmol/L (SR141716A: 32.16 nmol/L). WIN 55,212-2 (1 μmol/L) increased [Ca2+]i in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB1 cells. MJ08 (10 nmol/L–10 μmol/L) blocked both the WIN 55,212-2-induced effects. Furthermore, MJ08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA2=10.29±1.05). MJ08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle. MJ08 significantly increased the cAMP level in CHO-hCB1 cells with an EC50 value of 78.6 nmol/L, which was lower than the EC50 value for SR141716A (159.2 nmol/L). Besides the more potent pharmacological effects of cannabinoid CB1 receptor antagonism in DIO mice, such as reducing food intake, decreasing body weight, and ameliorating dyslipidemia, MJ08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo.
Conclusion:
MJ08 is a novel, potent and selective CB1 receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB1 receptors.
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References
Xie S, Furjanic MA, Ferrara JJ, McAndrew NR, Ardino EL, Ngondara A, et al. 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 use. J Clin Pharm Ther 2007; 32: 209–31.
Janero DR, Makriyannis A . Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin Emerg Drugs 2009; 14: 43–65.
Pertwee RG . Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 2009; 156: 397–411.
Di Marzo V, Szallasi A . Rimonabant in rats with a metabolic syndrome: good news after the depression. Br J Pharmacol 2008; 154: 915–7.
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.
Nisoli E, Carruba MO . Emerging aspects of pharmacotherapy for obesity and metabolic syndrome. Pharmacol Res 2004; 50: 453–69.
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.
Receveur JM, Murray A, Linget JM, Norregaard PK, Cooper M, Bjurling E, et al. 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.
Pertwee RG . Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 2005; 76: 1307–24.
Fong TM, Heymsfield SB . Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions. Int J Obes (Lond) 2009; 33: 947–55.
Rinaldi-Carmona M, Barth F, Heaulme M, Shire D, Calandra B, Congy C, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 1994; 350: 240–4.
Shearman LP, Stribling DS, Camacho RE, Rosko KM, Wang JY, Tong S, et al. Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents. Eur J Pharmacol 2008; 579: 215–24.
Sink KS, McLaughlin PJ, Wood JA, Brown C, Fan P, Vemuri VK, et al. The novel cannabinoid CB1 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.
Chen W, Tang H, Liu H, Long L, Gong Z, Zheng J, et al. Novel selective antagonist of the cannabinoid CB1 receptor, MJ15, with prominent anti-obesity effect in rodent models. Eur J Pharmacol 2010; 637: 178–85.
Jagerovic N, Hernandez-Folgado L, Alkorta I, Goya P, Navarro M, Serrano A, et al. 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.
Pertwee RG, Joe-Adigwe G, Hawksworth GM . Further evidence for the presence of cannabinoid CB1 receptors in mouse vas deferens. Eur J Pharmacol 1996; 296: 169–72.
Christopoulos A, Coles P, Lay L, Lew MJ, Angus JA . Pharmacological analysis of cannabinoid receptor activity in the rat vas deferens. Br J Pharmacol 2001; 132: 1281–91.
Chen W, Zhou XB, Liu HY, Xu C, Wang LL, Li S . P633H, a novel dual agonist at peroxisome proliferator-activated receptors alpha and gamma, with different anti-diabetic effects in db/db and KK-Ay mice. Br J Pharmacol 2009; 157: 724–35.
Hsieh C, Brown S, Derleth C, Mackie K . Internalization and recycling of the CB1 cannabinoid receptor. J Neurochem 1999; 73: 493–501.
Lauckner JE, Hille B, Mackie K . The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci U S A 2005; 102: 19144–9.
Wang H, Dey SK, Maccarrone M . Jekyll and hyde: two faces of cannabinoid signaling in male and female fertility. Endocr Rev 2006; 27: 427–48.
Bosier B, Muccioli GG, Hermans E, Lambert DM . Functionally selective cannabinoid receptor signalling: therapeutic implications and opportunities. Biochem Pharmacol 2010; 80: 1–12.
Drysdale AJ, Ryan D, Pertwee RG, Platt B . Cannabidiol-induced intracellular Ca2+ elevations in hippocampal cells. Neuropharmacology 2006; 50: 621–31.
Sugiura T, Kodaka T, Kondo S, Tonegawa T, Nakane S, Kishimoto S, et al. 2-arachidonoylglycerol, a putative endogenous cannabinoid receptor ligand, induces rapid, transient elevation of intracellular free Ca2+ in neuroblastoma X glioma hybrid NG108-15 cells. Biochem Biophys Res Commun 1996; 229: 58–64.
Di Marzo V, Capasso R, Matias I, Aviello G, Petrosino S, Borrelli F, et al. The role of endocannabinoids in the regulation of gastric emptying: alterations in mice fed a high-fat diet. Br J Pharmacol 2008; 153: 1272–80.
Hildebrandt AL, Kelly-Sullivan DM, Black SC . Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice. Eur J Pharmacol 2003; 462: 125–32.
Di Marzo V . The endocannabinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation. Pharmacol Res 2009; 60: 77–84.
Di Marzo V, Matias I . Endocannabinoid control of food intake and energy balance. Nat Neurosci 2005; 8: 585–9.
Griffith DA, Hadcock JR, Black SC, Iredale PA, Carpino PA, DaSilva-Jardine P, et al. Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperi dine-4-carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist. J Med Chem 2009; 52: 234–7.
Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001; 410: 822–5.
Rivera P, Romero-Zerbo Y, Pavon FJ, Serrano A, Lopez-Avalos MD, Cifuentes M, et al. Obesity-dependent cannabinoid modulation of proliferation in adult neurogenic regions. Eur J Neurosci 2011; 33: 1577–86.
Molhoj S, Hansen HS, Schweiger M, Zimmermann R, Johansen T, Malmlof K . Effect of the cannabinoid receptor-1 antagonist rimonabant on lipolysis in rats. Eur J Pharmacol 2010; 646: 38–45.
Thomas BF, Zhang Y, Brackeen M, Page KM, Mascarella SW, Seltzman HH . Conformational characteristics of the interaction of SR141716A with the CB1 cannabinoid receptor as determined through the use of conformationally constrained analogs. AAPS J 2006; 8: E665–71.
Acknowledgements
We gratefully acknowledge Prof Hua LI for her critical reading of the manuscript. This work was funded by Chinese National Hi-tech Research and Development Grants '863' (No 2003AA235010), the National Key Technologies R&D Program for New Drug of China (No 2009ZX09301-002) and the National Science and Technology Major Project of the Ministry of Science and Technology of China (No 2009ZX09501-031).
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Chen, W., Xu, C., Liu, Hy. et al. Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects. Acta Pharmacol Sin 32, 1148–1158 (2011). https://doi.org/10.1038/aps.2011.80
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DOI: https://doi.org/10.1038/aps.2011.80
