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

Abstract The effects of a novel adenosine A 3 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 [ N 6-(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 A 1 and A 2 adenosine receptors NECA [1-(6-amino-9 H -purin-9-yl)-1-deoxy- N -ethyl-b- d -ribofuranuronamide-5′- N -ethylcarboxamidoadenosine], R-PIA [ N 6 -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 (IC 50 =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 (ED 50 =0.008 mg/kg) or oral (ED 50 =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 EC 50 values of 0.33 mg/kg p.o., 0.02 mg/kg i.p. and 3 mg/kg i.p., respectively.