NESS038C6, a novel selective CB1 antagonist agent with anti-obesity activity and improved molecular profile

Behavioural Brain Research

Volumn 234, Issue 2, 2012, Pages 192-204

  Mastinu, Andrea ^a,b   Pira, Marilena ^a,c   Pani, Luca ^a,e   Pinna, Gérard Aimè ^c   Lazzari, Paolo ^c,d  

^a INSTITUTE OF TRANSLATIONAL PHARMACOLOGY   (Italy)

^b UNIVERSITY OF CAGLIARI   (Italy)

^c UNIVERSITY OF SASSARI   (Italy)

^d Neuroscienze Pharmaness Scarl ^*  (Italy)

^e ITALIAN MEDICINES AGENCY   (Italy)

Author keywords

Blood parameters; Dio mice; Leptin pathway; Monoaminergic transporters; NESS038C6; Neurotrophic factors

Indexed keywords

ADIPONECTIN; ANTIOBESITY AGENT; FATTY ACID SYNTHASE; LEPTIN; MESSENGER RNA; N PIPERIDINYL 7 BROMO 1 (2',4' DICHLOROPHENYL) 4,5 DIHYDRO 1H THIENOL[2,3 G]INDAZOL 3 CARBOXAMIDE; NESS 038C6; NEUROTROPHIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; RIMONABANT; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIOBESITY ACTIVITY; ARTICLE; BODY MASS; CALORIC INTAKE; CARDIOVASCULAR RISK; CONTROLLED STUDY; DRUG ACTIVITY; DRUG MECHANISM; GENE EXPRESSION; GENE EXPRESSION PROFILING; MALE; MONOAMINERGIC SYSTEM; MOUSE; NEUROTRANSMISSION; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; WEIGHT REDUCTION;

ANALYSIS OF VARIANCE; ANIMALS; ANTI-OBESITY AGENTS; BLOOD GLUCOSE; BODY MASS INDEX; BODY WEIGHT; BRAIN-DERIVED NEUROTROPHIC FACTOR; CANNABINOID RECEPTOR ANTAGONISTS; CHOLESTEROL; DIETARY FATS; DISEASE MODELS, ANIMAL; DOPAMINE PLASMA MEMBRANE TRANSPORT PROTEINS; DOSE-RESPONSE RELATIONSHIP, DRUG; GENE EXPRESSION REGULATION; HYPOTHALAMUS; INDAZOLES; INTRA-ABDOMINAL FAT; LIVER; MALE; MICE; MICE, INBRED C57BL; NERVE GROWTH FACTOR; OBESITY; PIPERIDINES; PYRAZOLES; RECEPTOR, CANNABINOID, CB1; SEROTONIN PLASMA MEMBRANE TRANSPORT PROTEINS; THIOPHENES; TRANSAMINASES; TRIGLYCERIDES;

EID: 84864057154     PISSN: 01664328     EISSN: 18727549     Source Type: Journal    
DOI: 10.1016/j.bbr.2012.06.033     Document Type: Article

References (72)

1. Assareh N., El Batsh M.M., Marsden C.A., Kendall D.A. The effects of chronic administration of tranylcypromine and rimonabant on behaviour and protein expression in brain regions of the rat. Pharmacology Biochemistry and Behavior 2012, 100:506-512.
2. Bensaid M., Gary-Bobo M., Esclangon A., Maffrand J.P., Le Fur G., Oury-Donat F., et al. The cannabinoid CB1 receptor antagonist SR 141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Molecular Pharmacology 2003, 63:908-914.
3. Berthoud H.R. Interactions between the " cognitive" and " metabolic" brain in the control of food intake. Physiology and Behavior 2007, 91:486-498.
4. Black S.C. Cannabinoid receptor antagonists and obesity. Current Opinion in Investigational Drugs 2004, 5:389-394.
5. Caraceni P., Pertosa A.M., Giannone F., Domenicali M., Grattagliano I., Principe A., et al. Antagonism of the cannabinoid CB-1 receptor protects rat liver against ischaemia-reperfusion injury complicated by endotoxaemia. Gut 2009, 58:1135-1143.
6. Chambers A.P., Sharkey K.A., Koopmans H.S. Cannabinoid (CB)1 receptor antagonist, AM 251, causes a sustained reduction of daily food intake in the rat. Physiology and Behavior 2004, 82:863-869.
7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analytical Biochemistry 1987, 162:156-159.
8. Colombo G., Agabio R., Diaz G., Lobina C., Reali R., Gessa G.L. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sciences 1998, 63:PL113-PL117.
9. Cota D. CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health. Diabetes/Metabolism Research and Reviews 2007, 23:507-517.
10. Cota D. Role of the endocannabinoid system in energy balance regulation and obesity. Frontiers of Hormone Research 2008, 36:135-145.
11. Cota D., Sandoval D.A., Olivieri M., Prodi E., D'Alessio D.A., Woods S.C., et al. Food intake-independent effects of CB1 antagonism on glucose and lipid metabolism. Obesity 2009, 17:1641-1645.
12. Di Marzo V., Goparaju S.K., Wang L., Liu J., Bátkai S., Járai Z., et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001, 410:822-825.
13. Di Marzo V., Piscitelli F., Mechoulam R. Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes. Handbook of Experimental Pharmacology 2011, 203:75-104.
14. Dietz W.H., Robinson T.N. Use of the body mass index (BMI) as a measure of overweight in children and adolescents. Journal of Pediatrics 1998, 132:191-193.
15. Egecioglu E., Skibicka K.P., Hansson C., Alvarez-Crespo M., Friberg P.A., Jerlhag E., et al. Hedonic and incentive signals for body weight control. Reviews in Endocrine and Metabolic Disorders 2011, 12:141-151.
16. Engeli S. Peripheral metabolic effects of endocannabinoids and cannabinoid receptor blockade. Obesity Facts 2008, 1:8-15.
17. Engeli S. Central and peripheral cannabinoid receptors as therapeutic targets in the control of food intake and body weight. Handbook of Experimental Pharmacology 2012, 209:357-381.
18. Esteban S., García-Sevilla J.A. Effects induced by cannabinoids on monoaminergic systems in the brain and their implications for psychiatric disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2011, [Epub ahead of print].
19. Gary-Bobo M., Elachouri G., Gallas J.F., Janiak P., Marini P., Ravinet-Trillou C., et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology 2007, 46:122-129.
20. Haslam D.W., James W.P. Obesity 2005, 366:1197-1209.
21. Hassanzadeh P., Rahimpour S. The cannabinergic system is implicated in the upregulation of central NGF protein by psychotropic drugs. Psychopharmacology 2011, 215:129-141.
22. Hildebrandt A.L., Kelly-Sullivan D.M., Black S.C. Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice. European Journal of Pharmacology 2003, 462:125-132.
23. Hochberg I., Hochberg Z. Expanding the definition of hypothalamic obesity. Obesity Reviews 2010, 11:709-721.
24. Horder J., Browning M., Di Simplicio M., Cowen P.J., Harmer C.J. Effects of 7 days of treatment with the cannabinoid type 1 receptor antagonist, rimonabant, on emotional processing. Journal of Psychopharmacology 2012, 26:125-132.
25. Hotta K., Funahashi T., Bodkin N.L., Ortmeyer H.K., Arita Y., Hansen B.C., et al. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 2001, 50:1126-1133.
26. Jbilo O., Ravinet-Trillou C., Arnone M., Buisson I., Bribes E., Peleraux A., et al. The CB1 receptor antagonist Rimonabant reverses the diet-induced obesity phenotype hrough the regulation of lipolysis and energy balance. FASEB Journal 2005, 19:1567-1569.
27. Jéquier E. Leptin signaling, adiposity, and energy balance. Annals of the New York Academy of Sciences 2002, 967:379-388.
28. Jourdan T., Djaouti L., Demizieux L., Gresti J., Vergès B., Degrace P. CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice. Diabetes 2010, 59:926-934.
29. Kishida K., Kim K.K., Funahashi T., Matsuzawa Y., Kang H.C., Shimomura I. Relationships between circulating adiponectin levels and fat distribution in obese subjects. Journal of Atherosclerosis and Thrombosis 2011, 18:592-595.
30. Kunos G., Tam J. The case for peripheral CB1 receptor blockade in the treatment of visceral obesity and its cardiometabolic complications. British Journal of Pharmacology 2011, 163:1423-1431.
31. Larsen P.J., Vrang N., Tang-Christensen M., Jensen P.B., Hay-Schmidt A., Rømer J., et al. Ups and downs for neuropeptides in body weight homeostasis: pharmacological potential of cocaine amphetamine regulated transcript and pre-proglucagon-derived peptides. European Journal of Pharmacology 2002, 440:159-172.
32. Laviolette S.R., Grace A.A. Cannabinoids potentiate emotional learning plasticity in neurons of the medial prefrontal cortex through basolateral amygdala inputs. Journal of Neuroscience 2006, 26:6458-6468.
33. Lazzari P, Ruiu S, Pinna GA, Murineddu G. Patent No.: US 7,485,730 B2; Feb 2009.
34. Lazzari P., Sanna A., Mastinu A., Cabasino S., Manca I., Pani L. Weight loss induced by rimonabant is associated with an altered leptin expression and hypothalamic leptin signaling in diet-induced obese mice. Behavioural Brain Research 2011, 217:432-438.
35. LoVerme J., Duranti A., Tontini A., Spadoni G., Mor M., Rivara S., et al. Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice. Bioorganic and Medicinal Chemistry Letters 2009, 19:639-643.
36. Maccarrone M., Gasperi V., Catani M.V., Diep T.A., Dainese E., Hansen H.S., et al. The endocannabinoid system and its relevance for nutrition. Annual Review of Nutrition 2010, 30:423-440.
37. Matias I., Gonthier M.P., Orlando P., Martiadis V., De Petrocellis L., Cervino C., et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. Journal of Clinical Endocrinology and Metabolism 2006, 91:3171-3180.
38. Matias I., Petrosino S., Racioppi A., Capasso R., Izzo A.A., Di Marzo V. Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: effect of high fat diets. Molecular and Cellular Endocrinology 2008, 286:S66-S78.
39. Nam D.H., Lee M.H., Kim J.E., Song H.K., Kang Y.S., Lee J.E., et al. Blockade of cannabinoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic nephropathy in db/db mice. Endocrinology 2012, 153:1387-1396.
40. Nathan P.J., O'Neill B.V., Napolitano A., Bullmore E.T. Neuropsychiatric adverse effects of centrally acting antiobesity drugs. CNS Neuroscience and Therapeutics 2011, 17:490-505.
41. Niswender K.D., Daws L.C., Avison M.J., Galli A. Insulin regulation of monoamine signaling: pathway to obesity. Neuropsychopharmacology 2011, 36:359-360.
42. Pang Z., Wu N.N., Zhao W., Chain D.C., Schaffer E., Zhang X., et al. The central cannabinoid CB1 receptor is required for diet-induced obesity and rimonabant's antiobesity effects in mice. Obesity 2011, 19:1923-1934.
43. Park H.R., Park M., Choi J., Park K.Y., Chung H.Y., Lee J. A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neuroscience Letters 2010, 482:235-239.
44. Poirier B., Bidouard J.P., Cadrouvele C., Marniquet X., Staels B., O'Connor S.E., et al. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes, Obesity and Metabolism 2005, 7:65-72.
45. Prasad H., Ryan D.A., Celzo M.F., Stapleton D. Metabolic syndrome: definition and therapeutic implications. Postgraduate Medicine 2012, 124:21-30.
46. Quarta C., Mazza R., Obici S., Pasquali R., Pagotto U. Energy balance regulation by endocannabinoids at central and peripheral levels. Trends in Molecular Medicine 2011, 17:518-526.
47. Ravinet Trillou C., Arnone M., Delgorge C., Gonalons N., Keane P., Maffrand J.P., et al. Anti-obesity effect of SR 141716, a CB1 receptor antagonist, in diet-induced obese mice. American Journal of Physiology - Regulatory, Integrative, and Comparative Physiology 2003, 284:R345-R353.
48. Ravinet Trillou C., Delgorge C., Menet C., Arnone M., Soubrié P. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. International Journal of Obesity and Related Metabolic Disorders 2004, 28:640-648.
49. Rigamonti A.E., Giordani C., Bonomo S.M., Cella S.G., Muller E.E. Early tolerance to the hypophagic effect of the cannabinoid receptor antagonist SR 141716 does not impede blockade of an orexigenic stimulus. European Journal of Pharmacology 2006, 542:116-120.
50. Robertson S.D., Matthies H.J., Owens W.A., Sathananthan V., Christianson N.S., Kennedy J.P., et al. Insulin reveals Akt signaling as a novel regulator of norepinephrine transporter trafficking and norepinephrine homeostasis. Journal of Neuroscience 2010, 30:11305-11316.
51. Sainsbury A., Zhang L. Role of the arcuate nucleus of the hypothalamus in regulation of body weight during energy deficit. Molecular and Cellular Endocrinology 2010, 316:109-119.
52. Scherer T., Buettner C. Yin and Yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism. Reviews in Endocrine and Metabolic Disorders 2011, 12:235-243.
53. Schwartz M.W., Woods S.C., Porte D., Seeley R.J., Baskin D.G. Central nervous system control of food intake. Nature 2000, 404:661-671.
54. Shamseddeen H., Getty J.Z., Hamdallah I.N., Ali M.R. Epidemiology and economic impact of obesity and type 2 diabetes. Surgical Clinics of North America 2011, 91:1163-1172.
55. Silvestri C., Ligresti A., Di Marzo V. Peripheral effects of the endocannabinoid system in energy homeostasis: adipose tissue, liver and skeletal muscle. Reviews in Endocrine and Metabolic Disorders 2011, 12:153-162.
56. Starowicz K.M., Cristino L., Matias I., Capasso R., Racioppi A., Izzo A.A., et al. Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with a high-fat diet. Obesity 2008, 16:553-565.
57. Tam J., Vemuri V.K., Liu J., Bátkai S., Mukhopadhyay B., Godlewski G., et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. Journal of Clinical Investigation 2010, 120:2953-2966.
58. Thornton-Jones Z.D., Vickers S.P., Clifton P.G. The cannabinoid CB1 receptor antagonist SR 141716A reduces appetitive and consummatory responses for food. Psychopharmacology 2005, 179:452-460.
59. Tonstad S., Després J.P. Treatment of lipid disorders in obesity. Expert Review of Cardiovascular Therapy 2011, 9:1069-1080.
60. Tovar A.R., Díaz-Villaseñor A., Cruz-Salazar N., Ordáz G., Granados O., Palacios-González B., et al. Dietary type and amount of fat modulate lipid metabolism gene expression in liver and in adipose tissue in high-fat diet-fed rats. Archives of Medical Research 2011, 42:540-553.
61. Valenzuela C.A., Castillo V.A., Aguirre C.A., Ronco A.M., Llanos M.N. The CB1 receptor antagonist SR 141716A reverses adult male mice overweight and metabolic alterations induced by early stress. Obesity 2011, 19:29-35.
62. Vemuri V.K., Janero D.R., Makriyannis A. Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome. Physiology and Behavior 2008, 93:671-686.
63. Verty A.N., Allen A.M., Oldfield B.J. The effects of rimonabant on brown adipose tissue in rat: implications for energy expenditure. Obesity 2009, 17:254-261.
64. Vickers S.P., Webster L.J., Wyatt A., Dourish C.T., Kennett G.A. Preferential effects of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats. Psychopharmacology 2003, 167:103-111.
65. Wu Y.K., Yeh C.F., Ly T.W., Hung M.S. A new perspective of cannabinoid 1 receptor antagonists: approaches toward peripheral CB1R blockers without crossing the blood-brain barrier. Current Topics in Medicinal Chemistry 2011, 11:1421-1429.
66. Xie S., Furjanic M.A., Ferrara J.J., McAndrew N.R., Ardino E.L., 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. Journal of Clinical Pharmacy and Therapeutics 2007, 32:209-231.
67. Yamada N., Katsuura G., Ochi Y., Ebihara K., Kusakabe T., Hosoda K., et al. Impaired CNS leptin action is implicated in depression associated with obesity. Endocrinology 2011, 152:2634-2643.
68. Yamauchi T., Kamon J., Waki H., Terauchi Y., Kubota N., Hara K., et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine 2001, 7:941-946.
69. You T., Disanzo B.L., Wang X., Yang R., Gong D. Adipose tissue endocannabinoid system gene expression: depot differences and effects of diet and exercise. Lipids in Health and Disease 2011, 10:194.
70. Zhang L.N., Gamo Y., Sinclair R., Mitchell S.E., Morgan D.G., Clapham J.C., et al. Effects of chronic oral rimonabant administration on energy budgets of diet-induced obese C57BL/6 mice. Obesity 2012, 20:954-962.
71. Zhang Y., Gilliam A., Maitra R., Damaj M.I., Tajuba J.M., Seltzman H.H., et al. Synthesis and biological evaluation of bivalent ligands for the cannabinoid 1 receptor. Journal of Medicinal Chemistry 2010, 53:7048-7060.
72. Zheng H., Lenard N.R., Shin A.C., Berthoud H.R. Appetite control and energy balance regulation in the modern world: reward-driven brain overrides repletion signals. International Journal of Obesity 2009, 33:S8-S13.