Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), in rodents.

Abstract

The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding K(i) of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma C(max) of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30-40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.

• Authors: Tung M Fong, Xiao-Ming Guan, Donald J Marsh, Chun-Pyn Shen, D Sloan Stribling, Kim M Rosko, Julie Lao, Hong Yu, Yue Feng, Jing C Xiao, Lex H T Van der Ploeg, Mark T Goulet, Williams K Hagmann, Linus S Lin, Thomas J Lanza Jr, James P Jewell, Ping Liu, Shrenik K Shah, Hongbo Qi, Xinchun Tong, Junying Wang, Suoyu S Xu, Barbara Francis, Alison M Strack, D Euan MacIntyre, Lauren P Shearman
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 321 Issue 3 Pg. 1013-22 (Jun 2007) ISSN: 0022-3565 [Print] United States
• PMID: 17327489 (Publication Type: Journal Article)

Chemical References

• 2-iodophenyl-(1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl)methanone
• Amides
• Anti-Obesity Agents
• Cyclohexanols
• Indoles
• Piperidines
• Pyridines
• Receptor, Cannabinoid, CB1
• Colforsin
• 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
• Cyclic AMP
• N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

Topics

• Amides (chemistry, metabolism, pharmacology)
• Animals
• Anti-Obesity Agents (chemistry, metabolism, pharmacology)
• Binding, Competitive (drug effects)
• Body Temperature (drug effects)
• Body Weight (drug effects)
• CHO Cells
• Colforsin (pharmacology)
• Cricetinae
• Cricetulus
• Cyclic AMP (metabolism)
• Cyclohexanols (pharmacology)
• Dose-Response Relationship, Drug
• Eating (drug effects)
• Humans
• Indoles (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Structure
• Obesity (drug therapy, metabolism, physiopathology)
• Piperidines (metabolism)
• Pyridines (chemistry, metabolism, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1 (genetics, metabolism, physiology)
• Transfection