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

Authors: Mukhopadhyay P, Baggelaar M, Erdelyi K, Cao Z, Cinar R, Fezza F, Ignatowska-Jankowska B, Wilkerson J, van Gils N, Hansen T, Ruben M, Soethoudt M, Heitman L, Kunos G, Maccarrone M, Lichtman A, Pacher P, van der Stelt M.
Publisher/Year: Br J Pharmacol. 2015 Sep 23.
Pub Med ID/Journal ID: PMID:26398481



Herei we characterize 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 2 receptor (CB2 R) agonist, using both in vitro and in vivo assays/models, including a clinically relevant murine model of nephropathy.


We investigated the effects of LEI-101 on CB2 R 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.


LEI-101 behaved as a partial CB2 R agonist in β-arrestin and GTPγS assays and was ~100-fold selective in CB2 R/CB1 R-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 to the brain. LEI-101 up to a dose of 60 mg/kg (p.o.) did not exert any CNS-mediated effects in the mice tetrad assay. LEI-101 (p.o. or i.p.) at 3 or 10 mg/kg dose-dependently prevented kidney dysfunction and/or morphological damage induced by cisplatin in mice. These protective effects were associated with improved renal histopathological injury, attenuated oxidative stress and inflammation in the kidney, and were absent in CB2 R knockout mice.


These results indicate that LEI-101 is a selective, largely peripherally restricted, orally available CB2 R agonist with therapeutic potential in diseases that are associated with inflammation and/or oxidative stress, including kidney disease. This article is protected by copyright. All rights reserved.