The novel, orally available and peripherally restricted selective cannabinoid CB 2 receptor agonist LEI‐101 prevents cisplatin‐induced nephrotoxicity

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 CB 2 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 CB 2 receptors using β ‐arrestin and GTP γ S assays and was ~100‐fold selective in CB 2 /CB 1 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 CB 2 receptor knockout mice. Conclusion and Implications These results indicate that LEI‐101 is a selective, largely peripherally restricted, orally available CB 2 receptor agonist with therapeutic potential in diseases that are associated with inflammation and/or oxidative stress, including kidney disease.