title: Selective activation of adenosine A2A receptors on immune cells by a CD73-dependent prodrug suppresses joint inflammation in experimental rheumatoid arthritis.
abstract: Adenosine A(2A) receptor (A(2A)R) agonists are both highly effective anti-inflammatory agents and potent vasodilators. To separate these two activities, we have synthesized phosphorylated A(2A)R agonists (prodrugs) that require the presence of ecto-5'-nucleotidase (CD73) to become activated. In the model of collagen-induced arthritis, 2-(cyclohexylethylthio)adenosine 5'-monophosphate (chet-AMP), but not 2-(cyclohexylethylthio)adenosine (chet-adenosine), potently reduced inflammation as assessed by fluorine-19 ((19)F) magnetic resonance imaging and by histology. The prodrug effect was blunted by inhibition of CD73 and A(2A)R. The selectivity of drug action is due to profound up-regulation of CD73 and adenosine A(2A)R expression in neutrophils and inflammatory monocytes as found in recovered cells from the synovial fluid of arthritic mice. Plasma chet-adenosine was in the subnanomolar range when chet-AMP was applied, whereas concentrations required for vasodilation were about 100 times higher. Thus, chet-AMP is a potent immunosuppressant with negligible vasodilatory activity. These data suggest that phosphorylated A(2A)R agonists may serve as a promising new group of drugs for targeted immunotherapy of inflammation.
authors.affiliation: Department of Molecular Cardiology, Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flögel
authors.forename: Sandra
authors.initials: S
authors.lastname: Burghoff
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.forename: Sebastian
authors.initials: S
authors.lastname: Temme
authors.forename: Lisa
authors.initials: L
authors.lastname: Galbarz
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Ding
authors.forename: Ali
authors.initials: A
authors.lastname: El-Tayeb
authors.forename: Sandra
authors.initials: S
authors.lastname: Huels
authors.forename: Florian
authors.initials: F
authors.lastname: Bönner
authors.forename: Nadine
authors.initials: N
authors.lastname: Borg
authors.forename: Christoph
authors.initials: C
authors.lastname: Jacoby
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schrader
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D058908:Adenosine A2 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D007596:Joints / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000627:therapeutic use*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D011355:Prodrugs; D043705:Receptor, Adenosine A2A; D015720:5'-Nucleotidase