MECHANISM-BASED PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE EFFECTS OF N-6-CYCLOPENTYLADENOSINE ANALOGS ON HEART-RATE IN RAT - ESTIMATION OF IN-VIVO OPERATIONAL AFFINITY AND EFFICACY AT ADENOSINE A(1) RECEPTORS

We have developed a pharmacokinetic-pharmacodynamic strategy based on the operational model of agonism to obtain estimates of apparent affin ity and efficacy of N-6-cyclopentyladenosine (CPA) analogs for the ade nosine A(1) receptor-mediated in vivo effect on heart rate in the rat. All analogs investigated produced a significant decrease of the heart rate after intravenous infusion. Individual concentration-effect curv es were fitted to the operational model of agonism with the values of E-max and n constrained to the intrinsic activity (273 bpm) and Hill s lope (1.18), respectively, obtained with the agonist that displayed th e highest intrinsic activity, 5'-deoxy-CPA. In all cases, the model co nverged and estimates of apparent affinity and efficacy were obtained for each agonist. Affinity estimates correlated well with pK(i) values for the adenosine A(1) receptor in rat brain homogenates. In addition , a highly significant correlation was found between the estimates of the in vivo efficacy parameter and the GTP shift (the ratio between K- i in the presence and absence of GTP). In conclusion, the operational model of agonism can provide meaningful measures of agonist affinity a nd efficacy at adenosine A, receptors in vivo. The model should be of use in the development of partial adenosine A(1) receptor agonists.