QUANTIFICATION OF THE IN-VIVO POTENCY OF THE ADENOSINE A(2) RECEPTOR ANTAGONIST 8-(3-CHLOROSTYRYL)CAFFEINE

The purpose of the present study was to quantify the in vivo potency of the selective adenosine A(2a) antagonist CSC [8-(3-chlorostyryl)caffeine]. Four groups of conscious, normotensive rats received a continuous i.v. infusion of 0, 6, 12 and 24 mu g/min/kg of CSC. During a steady-state infusion of CSC, the animals received 1000 mu g/kg of the adenosine A(2a) receptor agonist CGS 21680C [the sodium salt of 2-p-(2-carboxyethyl) phenytethylamino-5'-N-ethylcarboxamidoadenosine] i.v. over 15 min. During the experiment, the mean arterial pressure and the heart rate were recorded continuously and arterial blood samples were taken for the analysis of drug concentrations. For each individual rat, the CGS 21680C-provoked reduction in blood pressure was related to the blood concentration of the agonist according to the sigmoidal E(max) model. The presence of CSC produced a parallel shift of the concentration-hypotensive effect curve to the right, indicating competitive interaction of the compounds. Infusion of 0, 6, 12 and 24 mu g/min/kg of CSC resulted in steady-state concentrations of 0, 85 +/- 7, 210 +/- 20 and 400 +/- 40 ng/ml, and apparent EC(50) values of CGS 21680C based on free concentrations (EC(50,u)) of 4.8 +/- 1.1, 7.2 +/- 0.5, 32 +/- 6 and 57 +/- 10 ng/ml, respectively (mean +/- S.E., n = 6, 6, 5 and 6). The relationship between the CSC concentration and the apparent EC(50) was quantified according to a competitive pharmacodynamic interaction model. For the in vivo potency of CSC, an EC(50,u) value of 16 +/- 4 ng/ml (48 +/- 11 nM) was obtained, which was in agreement with the reported affinity of 54 nM, as determined in radioligand binding studies in vitro.