title: The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Bio-organic Synthesis, Leiden University, Leiden, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Baggelaar
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Erdelyi
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Zongxian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Department Experimental Medicine & Surgery, Tor Vergata University of Rome, Rome, Italy.|European Center for Brain Research/Santa Lucia Foundation, Rome, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: Fezza
authors.affiliation: Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Bogna
authors.initials: B
authors.lastname: Ignatowska-Janlowska
authors.affiliation: Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Wilkerson
authors.affiliation: Department of Medicinal Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Noortje
authors.initials: N
authors.lastname: van Gils
authors.affiliation: Department of Bio-organic Synthesis, Leiden University, Leiden, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hansen
authors.affiliation: Department of Bio-organic Synthesis, Leiden University, Leiden, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Ruben
authors.affiliation: Department of Bio-organic Synthesis, Leiden University, Leiden, The Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Soethoudt
authors.affiliation: Department of Medicinal Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Heitman
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.affiliation: European Center for Brain Research/Santa Lucia Foundation, Rome, Italy.|Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.affiliation: Department Experimental Medicine & Surgery, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Aron
authors.initials: A
authors.lastname: Lichtman
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Department of Bio-organic Synthesis, Leiden University, Leiden, The Netherlands.
authors.forename: Mario
authors.initials: M
authors.lastname: Van der Stelt
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D002945:Cisplatin / Q000009:adverse effects; D003412:Cricetulus; D053938:DNA Fragmentation; D048289:Imidazolidines / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D020011:Protective Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000235:genetics
chemical_list: C000611821:3-cyclopropyl-1-(4-(6-((1,1-dioxidothiomorpholino)methyl)-5-fluoropyridin-2-yl)benzyl)imidazolidine-2,4-dione hydrochloride; D048289:Imidazolidines; D009025:Morpholines; D020011:Protective Agents; D017382:Reactive Oxygen Species; D043885:Receptor, Cannabinoid, CB2; D002945:Cisplatin