2. Academic Validation
  3. The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity

The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity

  • Br J Pharmacol. 2016 Feb;173(3):446-58. doi: 10.1111/bph.13338.
Partha Mukhopadhyay 1,  Marc Baggelaar 2,  Katalin Erdelyi 1,  Zongxian Cao 1,  Resat Cinar 1,  Filomena Fezza 3 4,  Bogna Ignatowska-Janlowska 5,  Jenny Wilkerson 5,  Noortje van Gils 6,  Thomas Hansen 2,  Marc Ruben 2,  Marjolein Soethoudt 2,  Laura Heitman 6,  George Kunos 1,  Mauro Maccarrone 4 7,  Aron Lichtman 3,  Pál Pacher 1,  Mario Van der Stelt 2
Affiliations

Affiliations

  • 1 National Institutes of Health, Bethesda, MD, USA.
  • 2 Department of Bio-organic Synthesis, Leiden University, Leiden, The Netherlands.
  • 3 Department Experimental Medicine & Surgery, Tor Vergata University of Rome, Rome, Italy.
  • 4 European Center for Brain Research/Santa Lucia Foundation, Rome, Italy.
  • 5 Virginia Commonwealth University, Richmond, VA, USA.
  • 6 Department of Medicinal Chemistry, Leiden University, Leiden, The Netherlands.
  • 7 Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.
PMID: 26398481 DOI: 10.1111/bph.13338
Abstract

Background and purpose: Here, we have characterized 3-cyclopropyl-1-(4-(6-((1,1-dioxidothiomorpholino)methyl)-5-fluoropyridin-2-yl)benzyl)imidazolidine-2,4-dione hydrochloride (LEI-101) as a novel, peripherally restricted cannabinoid CB2 receptor agonist, using both in vitro and in vivo models.

Experimental approach: We investigated the effects of LEI-101 on binding and functional activity. We assessed its in vitro and in vivo selectivity. Efficacy of LEI-101 was determined in a mouse model of cisplatin-induced nephrotoxicity.

Key results: LEI-101 behaved as a partial agonist at CB2 receptors using β-arrestin and GTPγS assays and was ~100-fold selective in CB2 /CB1 receptor-binding assays. It did not display any activity on endocannabinoid hydrolases and nor did it react with serine hydrolases in an activity-based protein profiling assay. In mice, LEI-101 had excellent oral bioavailability reaching high concentrations in the kidney and liver with minimal penetration into the brain. LEI-101 up to a dose of 60 mg·kg(-1) (p.o.) did not exert any CNS-mediated effects in the tetrad assay, in mice. LEI-101 (p.o. or i.p.) at 3 or 10 mg·kg(-1) dose-dependently prevented kidney dysfunction and/or morphological damage induced by cisplatin in mice. These protective effects were associated with improved renal histopathology, attenuated oxidative stress and inflammation in the kidney. These effects were absent in CB2 receptor knockout mice.

Conclusion and implications: These results indicate that LEI-101 is a selective, largely peripherally restricted, orally available CB2 receptor agonist with therapeutic potential in diseases that are associated with inflammation and/or oxidative stress, including kidney disease.

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