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
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DOI：
10.1111/bph.13338
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发表时间：
2016-02-01
影响因子：
7.3
通讯作者：
Van der Stelt, Mario
中科院分区：
文献类型：
--
作者：
Mukhopadhyay, Partha;Baggelaar, Marc;Van der Stelt, Mario
Background and PurposeHere, 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 ApproachWe 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 beta- arrestin and GTP gamma S 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 center dot 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 center dot 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 ImplicationsThese 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.
