title: Pharmacological characterisation and inhibitory effects of (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol, a novel ligand that demonstrates both adenosine A(2A) receptor agonist and adenosine A(3) receptor antagonist activity.
abstract: The pharmacological properties of the novel ligand, (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol (I), at the human adenosine receptors were investigated using Chinese hamster ovary cell lines recombinantly expressing these receptors. Functional studies were performed using a cyclic AMP-coupled reporter gene system. Binding studies were performed using membranes from these cells. The effects of ligand (I) were also determined on functional responses of human neutrophils and eosinophils. Ligand (I) had a high affinity for the adenosine A(2A) receptor (pKi 7.8+/-0.2) and was a potent agonist at this receptor (pEC(50) 9.0+/-0.2). Ligand (I) had a similar affinity for the adenosine A(3) receptor (pKi 7.8+/-0.1) but displayed no agonist activity, acting instead as a competitive antagonist (pA(2) 8.3+/-0.04). Ligand (I) had lower affinity for adenosine A(1) and A(2B) receptors (pKi</=6) and showed relatively weak agonist activity at these receptors (pEC(50) 7.1 at both receptors). Ligand (I) was a potent inhibitor of the generation of reactive oxygen species from human neutrophils and eosinophils (pEC(50) 9.7+/-0.1 and 9.4+/-0.2 respectively). The inhibitory effect of ligand (I) on the release of reactive oxygen species from neutrophils was antagonised competitively by the adenosine A(2A) receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS15943) with a pA(2) value (10.03+/-0.44) consistent with an effect on adenosine A(2A) receptors. Ligand (I) also inhibited the release of granule proteins from neutrophils and eosinophils (pEC(50) 8.7 and 8.9 respectively), albeit less potently than as an inhibitor of reactive oxygen species generation. In summary, ligand (I) is a potent and selective agonist for the adenosine A(2A) receptor and a competitive antagonist at the adenosine A(3) receptor. Ligand (I) has potent anti-inflammatory effects on human granulocytes in vitro.
authors: Department of Screening and Compound Profiling, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, UK.
authors: Nicola
authors: N
authors: Bevan
authors: Peter R
authors: PR
authors: Butchers
authors: Rick
authors: R
authors: Cousins
authors: Jill
authors: J
authors: Coates
authors: Emma V
authors: EV
authors: Edgar
authors: Val
authors: V
authors: Morrison
authors: Michael J
authors: MJ
authors: Sheehan
authors: Julian
authors: J
authors: Reeves
authors: David J
authors: DJ
authors: Wilson
mesh_terms: D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology*; D011869:Radioligand Assay; D017382:Reactive Oxygen Species / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000187:drug effects; D043704:Receptor, Adenosine A2B / Q000187:drug effects; D043684:Receptor, Adenosine A3 / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C522066:(2R,3R,4S,5R)-2-(6-amino-2-(((1S)-2-hydroxy-1-(phenylmethyl)ethyl)amino)-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D011687:Purines; D017382:Reactive Oxygen Species; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D013777:Tetrazoles; D000242:Cyclic AMP