TY - JOUR T1 - Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of the Effects of N<sup>6</sup>-Cyclopentyladenosine Analogs on Heart Rate in Rat: Estimation of <em>in Vivo</em> Operational Affinity and Efficacy at Adenosine A<sub>1</sub> Receptors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 809 LP - 816 VL - 283 IS - 2 AU - P. H. Van Der Graaf AU - E. A. Van Schaick AU - R. A. A. Mathôt AU - A. P. Ijzerman AU - M. Danhof Y1 - 1997/11/01 UR - http://jpet.aspetjournals.org/content/283/2/809.abstract N2 - We have developed a pharmacokinetic-pharmacodynamic strategy based on the operational model of agonism to obtain estimates of apparent affinity and efficacy of N6-cyclopentyladenosine (CPA) analogs for the adenosine A1 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 curves were fitted to the operational model of agonism with the values ofEmax and n constrained to the intrinsic activity (273 bpm) and Hill slope (1.18), respectively, obtained with the agonist that displayed the highest intrinsic activity, 5′-deoxy-CPA. In all cases, the model converged and estimates of apparent affinity and efficacy were obtained for each agonist. Affinity estimates correlated well with pKi values for the adenosine A1 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 Ki in the presence and absence of GTP). In conclusion, the operational model of agonism can provide meaningful measures of agonist affinity and efficacy at adenosine A1 receptors in vivo. The model should be of use in the development of partial adenosine A1receptor agonists. The American Society for Pharmacology and Experimental Therapeutics ER -