Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models

The effects of a novel adenosine A3 receptor antagonist, SSR161421, were examined on both antigen per se and adenosine receptor agonist-increased airway responses in antigen-sensitized guinea pigs. Adenosine (10−5 M) and AB-MECA [N6-(4-aminobenzyl)-adenosine-5′-N-methyl-uronamide dihydrochloride] (10−7 M) increased the antigen response up to 61±3.0% and 88±5.2% of maximal contraction, respectively. The agonists of adenosine A1 and A2 adenosine receptors NECA [1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-b-d-ribofuranuronamide-5′-N-ethylcarboxamidoadenosine], R-PIA [N6-R-phenylisopropyladenosine], and CGS21680 (10−7 M) were ineffective. In vivo intravenous adenosine (600 μg/kg) and AB-MECA (30 μg/kg) increased the threshold antigen dose-induced bronchoconstriction by 214±13.0% and 220±15.2%, respectively. SSR161421 in vitro (IC50=5.9×10−7 M) inhibited the AB-MECA-enhanced antigen-induced airway smooth muscle contractions and also in vivo the bronchoconstriction following either intravenous (ED50=0.008 mg/kg) or oral (ED50=0.03 mg/kg) administration in sensitized guinea pigs. Antigen itself could evoke tracheal contraction in vitro and bronchoconstriction in vivo in antigen-sensitized guinea pigs. SSR161421 (3×10−6 M) decreased the AUC of the antigen-induced contraction-time curve to 20.8±5.4% from the 100% control level. SSR161421 effectively reversed the antigen-induced bronchoconstriction, plasma leak and cell recruitment with EC50 values of 0.33 mg/kg p.o., 0.02 mg/kg i.p. and 3 mg/kg i.p., respectively.