Agents which elevate intracellular cyclic AMP such as PDE4 inhibitors and adenosine A_2A receptor agonists (Thiel et al, 2003; Boswell-Smith et al, 2006) inhibit many pro-inflammatory functions of leukocytes. Here we report on the in vitro profile of the novel adenosine A_2A agonist UK-371,104 against release of a range of inflammatory mediators in the human isolated neutrophil. The pharmacological profile has been compared with the standard adenosine A_2A agonist CGS-21,680 (Jarvis et al, 1989) and the PDE4 inhibitor cilomilast (Boswell-Smith et al, 2006). Functional adenosine receptor selectivity of UK-371104 (9-[ (2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide) was assessed in recombinant human A_2A, A_2B , A₃ receptor transfected HEK-293 cells and A₁ transfected CHO cells. A_2A and A_2B potencies were quantified by EC₅₀ for stimulation of cAMP formation and A₁ and A₃ potencies by IC₅₀ for suppression of forskolin stimulated cAMP formation, measured by ELISA. UK-371,104 potencies (nM) were 20.1 (10.1-30.0), 4358 (2177-6540), 103.0 (54-102) and >1000 at A_2A, A_2B, A₁ and A₃ respectively. Data are geometric means ± 95% confidence interval (CI), n= 8-12. UK-371,104 was significantly more potent at A_2A compared with all other adenosine receptors (p<0.05 unpaired t test). Human neutrophils were isolated from healthy volunteers by density gradient centrifugation (Hatzelmann and Ullrich, 1987). All assays were carried out in 96 well format in HBSS buffer, pH7.4. Compounds were pre-incubated with neutrophils for 10 minutes, followed by stimulation with fMLP (30nM-1μM). Elastase and superoxide release were measured by chromogenic substrate cleavage and cytochrome C reduction, respectively. Leukotriene B₄ (LTB₄) biosynthesis was measured by ELISA. UK-371,104 and CGS-21,680 produced near maximal inhibition of release of all 3 mediators with similar potencies (p>0.05 unpaired t test), whereas cilomilast only inhibited LTB₄ biosynthesis and was significantly more potent than both A_2A agonists (p<0.05) – Table1. These results demonstrate that UK-371,104 is a selective adenosine A_2A agonist that elicits broad spectrum inhibition of acute mediator release in the isolated human neutrophil. Agents such as UK-371,104 might have therapeutic utility for the treatment of lung inflammation