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Peripherally Selective CB1 Receptor Antagonist Improves Symptoms of Metabolic Syndrome in Mice

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    Peripherally Selective CB1 Receptor Antagonist Improves Symptoms of Metabolic Syndrome in Mice
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    • Nayaab Khan
      Nayaab Khan
      Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
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    • Lucas Laudermilk
      Lucas Laudermilk
      Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
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    • Jalen Ware
      Jalen Ware
      Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
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    • Taylor Rosa
      Taylor Rosa
      Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
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    • Kelly Mathews
      Kelly Mathews
      Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
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    • Elaine Gay
      Elaine Gay
      Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
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    • George Amato
      George Amato
      Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
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    • Rangan Maitra*
      Rangan Maitra
      Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
      *Phone: 919-541-6795. Fax: 919-541-6499. Email: [email protected]
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      Orcidhttp://orcid.org/0000-0001-6663-6800
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    ACS Pharmacology & Translational Science

    Cite this: ACS Pharmacol. Transl. Sci. 2021, 4, 2, 757–764
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    https://doi.org/10.1021/acsptsci.0c00213
    Published March 9, 2021
    Copyright © 2021 American Chemical Society
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    Abstract

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    Metabolic syndrome (MetS) is a complex disorder that stems from the additive effects of multiple underlying causes such as obesity, insulin resistance, and chronic low-grade inflammation. The endocannabinoid system plays a central role in appetite regulation, energy balance, lipid metabolism, insulin sensitivity, and β-cell function. The type 1 cannabinoid receptor (CB1R) antagonist SR141716A (rimonabant) showed promising antiobesity effects, but its use was discontinued due to adverse psychiatric events in some users. These adverse effects are due to antagonism of CB1R in the central nervous system (CNS). As such, CNS-sparing CB1R antagonists are presently being developed for various indications. In this study, we report that a recently described compound, 3-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}-1-[6-(difluoromethoxy)pyridin-3-yl]urea (RTI1092769), a pyrazole based weak inverse agonist/antagonist of CB1 with very limited brain exposure, improves MetS related complications. Treatment with RTI1092769 inhibited weight gain and improved glucose utilization in obese mice maintained on a high fat diet. Hepatic triglyceride content and steatosis significantly improved with treatment. These phenotypes were supported by improvement in several biomarkers associated with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). These results reinforce the idea that CB1 antagonists with limited brain exposure should be pursued for MetS and other important indications.

    Copyright © 2021 American Chemical Society

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    This article is cited by 15 publications.

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    4. Hyekyung Yang, Miey Park, Ji Hye Lee, Bokyoung Kim, Chang Sang Moon, Suyeal Bae, Younghoon Kim, Hae-Jeung Lee, Cheol-Young Park. New peripherally-restricted CB1 receptor antagonists, PMG-505–010 and −013 ameliorate obesity-associated NAFLD and fibrosis. Biomedicine & Pharmacotherapy 2024, 180 , 117501. https://doi.org/10.1016/j.biopha.2024.117501
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    6. Nitzan Sharon, Ludmila Yarmolinsky, Boris Khalfin, Sigal Fleisher-Berkovich, Shimon Ben-Shabat. Cannabinoids’ Role in Modulating Central and Peripheral Immunity in Neurodegenerative Diseases. International Journal of Molecular Sciences 2024, 25 (12) , 6402. https://doi.org/10.3390/ijms25126402
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    8. Si Chen, Jeon-Kyung Kim. The Role of Cannabidiol in Liver Disease: A Systemic Review. International Journal of Molecular Sciences 2024, 25 (4) , 2370. https://doi.org/10.3390/ijms25042370
    9. Anindya Ghosh, Marie-Line Peyot, Yat Hei Leung, François Ravenelle, S R Murthy Madiraju, Marc Prentki. A peripherally restricted cannabinoid-1 receptor inverse agonist promotes insulin secretion and protects from cytokine toxicity in human pancreatic islets. European Journal of Pharmacology 2023, 944 , 175589. https://doi.org/10.1016/j.ejphar.2023.175589
    10. Tangui Barré, Vincenzo Di Marzo, Fabienne Marcellin, Patrizia Burra, Patrizia Carrieri. Expanding Research on Cannabis-Based Medicines for Liver Steatosis: A Low-Risk High-Reward Way Out of the Present Deadlock?. Cannabis and Cannabinoid Research 2023, 8 (1) , 5-11. https://doi.org/10.1089/can.2022.0014
    11. Kathryn Miranda, William Becker, Philip B. Busbee, Nicholas Dopkins, Osama A. Abdulla, Yin Zhong, Jiajia Zhang, Mitzi Nagarkatti, Prakash S. Nagarkatti. Yin and yang of cannabinoid CB1 receptor: CB1 deletion in immune cells causes exacerbation while deletion in non-immune cells attenuates obesity. iScience 2022, 25 (9) , 104994. https://doi.org/10.1016/j.isci.2022.104994
    12. Ralph-Sydney Mboumba Bouassa, Giada Sebastiani, Vincenzo Di Marzo, Mohammad-Ali Jenabian, Cecilia T. Costiniuk. Cannabinoids and Chronic Liver Diseases. International Journal of Molecular Sciences 2022, 23 (16) , 9423. https://doi.org/10.3390/ijms23169423
    13. Meirigeng Qi, John S. Kaddis, Kuan-Tsen Chen, Jeffrey Rawson, Keiko Omori, Zhen Bouman Chen, Sangeeta Dhawan, Jeffrey S. Isenberg, Fouad Kandeel, Bart O. Roep, Ismail H. Al-Abdullah, . Chronic marijuana usage by human pancreas donors is associated with impaired islet function. PLOS ONE 2021, 16 (10) , e0258434. https://doi.org/10.1371/journal.pone.0258434
    14. Inês Sousa-Lima, Hyun Jeong Kim, John Jones, Young-Bum Kim. Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases. Diabetes & Metabolism Journal 2021, 45 (5) , 655-674. https://doi.org/10.4093/dmj.2021.0197
    15. Luciana M. Leo, Mary E. Abood. CB1 Cannabinoid Receptor Signaling and Biased Signaling. Molecules 2021, 26 (17) , 5413. https://doi.org/10.3390/molecules26175413
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    ACS Pharmacology & Translational Science

    Cite this: ACS Pharmacol. Transl. Sci. 2021, 4, 2, 757–764
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsptsci.0c00213
    Published March 9, 2021
    Copyright © 2021 American Chemical Society
    Request reuse permissions

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