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

@article{Fong2007AntiobesityEO,
  title={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},
  author={Tung Ming Fong and Xiao-ming Guan and Donald J. Marsh and Chun-Pyn Shen and D. Sloan Stribling and Kim Rosko and Julie Z. Lao and Hong Yu and Yue Feng and Jing Chen Xiao and Lex H. T. van der Ploeg and Mark T. Goulet and William K. Hagmann and Linus Shouzhong Lin and Thomas J. Lanza and James P. Jewell and Ping-Hua Liu and Shrenik K. Shah and Hongbo Qi and Xinchun S Tong and Junying Wang and Suoyu S. Xu and Barbara Francis and Alison M. Strack and D. Euan Macintyre and Lauren P. Shearman},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2007},
  volume={321},
  pages={1013 - 1022}
}
  • T. Fong, X. Guan, L. Shearman
  • Published 1 June 2007
  • Biology, Chemistry, Medicine
  • Journal of Pharmacology and Experimental Therapeutics
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… 
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TLDR
The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, allowed the identification of benzodioxoles as a novelCB1R inverse agonist series, showing in vivo activity.
Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists.
  • R. Pertwee
  • Biology, Chemistry
    Current medicinal chemistry
  • 2010
TLDR
This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB(1), non- CB(2) G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner.
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Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity.
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TLDR
Chinese hamster ovary cells transfected with human central cannabinoid receptor (CB1) exhibit high constitutive activity at both levels of mitogen-activated protein kinase (MAPK) and adenylyl cyclase, and the CB1-selective ligand, SR 141716A, that functions as an inverse agonist is proposed as a novel model for receptor/ligand interactions.
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