The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity
| Autor: | Mukhopadhyay, P., Baggelaar, M., Erdelyi, K., Cao, Z., Cinar, R., Fezza, F., Ignatowska-Jankowska, B., Wilkerson, J., Gils, N. van, Hansen, T., Ruben, M., Soethoudt, M., Heitman, L., Kunos, G., Maccarrone, M., Lichtman, A., Pacher, P., Stelt, M. van der |
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| Přispěvatelé: | Chemistry and Pharmaceutical Sciences, Hematology laboratory |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Oral
Male Knockout Morpholines Apoptosis CHO Cells DNA Fragmentation Administration Oral Animals Cisplatin Cricetulus Imidazolidines Kidney Kidney Diseases Lipid Peroxidation Mice Inbred C57BL Mice Inbred ICR Mice Knockout Protective Agents Reactive Oxygen Species Receptor Cannabinoid CB2 Inbred C57BL Mice SDG 3 - Good Health and Well-being Settore BIO/10 Cannabinoid Inbred ICR CB2 Administration Receptor |
| Zdroj: | Mukhopadhyay, P, Baggelaar, M, Erdelyi, K, Cao, Z, Cinar, R, Fezza, F, Ignatowska-Janlowska, 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 2016, ' The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity ', British Journal of Pharmacology, vol. 173, no. 3, pp. 446-58 . https://doi.org/10.1111/bph.13338 British Journal of Pharmacology, 173(3), 446-458. Wiley-Blackwell Mukhopadhyay, P, Baggelaar, M, Erdelyi, K, Cao, Z, Cinar, R, Fezza, F, Ignatowska-Janlowska, 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 2016, ' The novel, orally available and peripherally restricted selective cannabinoid CB 2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity ', British Journal of Pharmacology, vol. 173, no. 3, pp. 446-458 . https://doi.org/10.1111/bph.13338 British Journal of Pharmacology, 173(3), 446-58. Wiley-Blackwell British Journal of Pharmacology, 173(3), 446–458 |
| ISSN: | 0007-1188 |
| DOI: | 10.1111/bph.13338 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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