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

Partha Mukhopadhyay, Marc Baggelaar, Katalin Erdelyi, Zongxian Cao, Resat Cinar, Filomena Fezza, Bogna Ignatowska-Janlowska, Jenny Wilkerson, Noortje van Gils, Thomas Hansen, Marc Ruben, Marjolein Soethoudt, Laura Heitman, George Kunos, Mauro Maccarrone, Aron Lichtman, Pál Pacher, Mario Van der Stelt

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)446-58
Number of pages13
JournalBritish Journal of Pharmacology
Volume173
Issue number3
DOIs
Publication statusPublished - Feb 2016

Cite this

Mukhopadhyay, Partha ; Baggelaar, Marc ; Erdelyi, Katalin ; Cao, Zongxian ; Cinar, Resat ; Fezza, Filomena ; Ignatowska-Janlowska, Bogna ; Wilkerson, Jenny ; van Gils, Noortje ; Hansen, Thomas ; Ruben, Marc ; Soethoudt, Marjolein ; Heitman, Laura ; Kunos, George ; Maccarrone, Mauro ; Lichtman, Aron ; Pacher, Pál ; Van der Stelt, Mario. / The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity. In: British Journal of Pharmacology. 2016 ; Vol. 173, No. 3. pp. 446-58.
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title = "The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity",
abstract = "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.",
keywords = "Administration, Oral, Animals, Apoptosis/drug effects, CHO Cells, Cisplatin/adverse effects, Cricetulus, DNA Fragmentation, Imidazolidines/chemistry, Kidney/drug effects, Kidney Diseases/chemically induced, Lipid Peroxidation/drug effects, Male, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Knockout, Morpholines/chemistry, Protective Agents/pharmacokinetics, Reactive Oxygen Species/metabolism, Receptor, Cannabinoid, CB2/agonists",
author = "Partha Mukhopadhyay and Marc Baggelaar and Katalin Erdelyi and Zongxian Cao and Resat Cinar and Filomena Fezza and Bogna Ignatowska-Janlowska and Jenny Wilkerson and {van Gils}, Noortje and Thomas Hansen and Marc Ruben and Marjolein Soethoudt and Laura Heitman and George Kunos and Mauro Maccarrone and Aron Lichtman and P{\'a}l Pacher and {Van der Stelt}, Mario",
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doi = "10.1111/bph.13338",
language = "English",
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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

The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity. / Mukhopadhyay, Partha; Baggelaar, Marc; Erdelyi, Katalin; Cao, Zongxian; Cinar, Resat; Fezza, Filomena; Ignatowska-Janlowska, Bogna; Wilkerson, Jenny; van Gils, Noortje; Hansen, Thomas; Ruben, Marc; Soethoudt, Marjolein; Heitman, Laura; Kunos, George; Maccarrone, Mauro; Lichtman, Aron; Pacher, Pál; Van der Stelt, Mario.

In: British Journal of Pharmacology, Vol. 173, No. 3, 02.2016, p. 446-58.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity

AU - Mukhopadhyay, Partha

AU - Baggelaar, Marc

AU - Erdelyi, Katalin

AU - Cao, Zongxian

AU - Cinar, Resat

AU - Fezza, Filomena

AU - Ignatowska-Janlowska, Bogna

AU - Wilkerson, Jenny

AU - van Gils, Noortje

AU - Hansen, Thomas

AU - Ruben, Marc

AU - Soethoudt, Marjolein

AU - Heitman, Laura

AU - Kunos, George

AU - Maccarrone, Mauro

AU - Lichtman, Aron

AU - Pacher, Pál

AU - Van der Stelt, Mario

N1 - Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

PY - 2016/2

Y1 - 2016/2

N2 - 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.

AB - 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.

KW - Administration, Oral

KW - Animals

KW - Apoptosis/drug effects

KW - CHO Cells

KW - Cisplatin/adverse effects

KW - Cricetulus

KW - DNA Fragmentation

KW - Imidazolidines/chemistry

KW - Kidney/drug effects

KW - Kidney Diseases/chemically induced

KW - Lipid Peroxidation/drug effects

KW - Male

KW - Mice, Inbred C57BL

KW - Mice, Inbred ICR

KW - Mice, Knockout

KW - Morpholines/chemistry

KW - Protective Agents/pharmacokinetics

KW - Reactive Oxygen Species/metabolism

KW - Receptor, Cannabinoid, CB2/agonists

U2 - 10.1111/bph.13338

DO - 10.1111/bph.13338

M3 - Article

VL - 173

SP - 446

EP - 458

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 3

ER -