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

Autor:	Mukhopadhyay, Partha, Baggelaar, Marc, Erdelyi, Katalin, Cao, Zongxian, Cinar, Resat, Fezza, Filomena, Ignatowska ‐ Janlowska, Bogna, Wilkerson, Jenny, Gils, Noortje, Hansen, Thomas, Ruben, Marc, Soethoudt, Marjolein, Heitman, Laura, Kunos, George, Maccarrone, Mauro, Lichtman, Aron, Pacher, Pál, Van der Stelt, Mario, Ignatowska-Janlowska, Bogna, van Gils, Noortje
Předmět:	ORAL medication CANNABINOID receptors CISPLATIN NEPHROTOXICOLOGY OXIDATIVE stress IN vitro studies PREVENTION REACTIVE oxygen species ANIMAL experimentation APOPTOSIS CELL receptors COMPARATIVE studies DNA HETEROCYCLIC compounds IMIDAZOLES KIDNEYS KIDNEY diseases RESEARCH methodology MEDICAL cooperation LIPID peroxidation (Biology) MICE ORAL drug administration PREVENTIVE health services RESEARCH RESEARCH funding RODENTS EVALUATION research PHARMACODYNAMICS
Zdroj:	British Journal of Pharmacology; Feb2016, Vol. 173 Issue 3, p446-458, 13p
Abstrakt:	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. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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