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Inhibition of alcoholic steatosis by a type 1 cannabinoid receptor antagonist ESBRA 2015 Meeting Abstract P-16

Past reports suggest that antagonism of the CB1 receptor (CB1R) is an emerging strategy to alcoholic liver disease. Unfortunately, first generation inverse agonists of CB1R have serious psychiatric side effects and are no longer in clinical use or development. However, neutral antagonists or CNS-sparing peripherally restricted antagonists of CB1R may be useful for ALD as these compounds should have limited adverse effects. We have recently developed N-{1-[8-(2-chlorophenyl)-9-(4-18 chlorophenyl)-9H-purin-6-yl]piperidin-4-yl} pentanamide (RTI-13329-173B), a potent antagonist of CB1R (Ki < 10 nM, >50-fold selective for CB1R over CB2R) with limited brain penetration (<10%). Further, this compound was deemed to be very stable in both plasma and hepatic fractions and devoid of any significant hERG channel interaction. This compound was tested in a rat model of alcoholic steatosis (AS) induced by liquid ethanol containing Lieber DeCarli diet. Accumulation of lipids in liver, levels of liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT) and triglycerides were increased in male Sprague Dawley rats fed the ethanol containing diet for 5 weeks. Treatment of pair-fed animals with 3 mg/kg RTI-13329-173B delivered once-daily orally led to decreased levels of circulating AST and ALT levels, lowered liver triglycerides levels, and decreased hepatic steatosis. In summary, RTI-13329-173B and other such peripherally selective CB1R antagonists should be further developed and investigated for alcoholic liver disease. (Funded by NIAAA, NIH).

Citation

Maitra, R., Fulp, A., Snyder, R., Fennell, T., Bortoff, K., & Zhang, Y. (2015). Inhibition of alcoholic steatosis by a type 1 cannabinoid receptor antagonist: ESBRA 2015 Meeting Abstract P-16. Alcohol and Alcoholism, 50(Suppl. 1), i49. DOI: 10.1093/alcalc/agv080.16

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