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Vol. 283, Issue 2, 809-816, 1997

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of the Effects of N6-Cyclopentyladenosine Analogs on Heart Rate in Rat: Estimation of in Vivo Operational Affinity and Efficacy at Adenosine A1 Receptors

P. H. Van Der Graaf, E. A. Van Schaick, R. A. A. Mathôt, A. P. Ijzerman and M. Danhof

Leiden/Amsterdam Center for Drug Research, Divisions of Pharmacology (P.H.V.D.G., E.V.S., R.A.A.M., M.D.) and Medicinal Chemistry (A.P.IJ.), 2300RA Leiden, The Netherlands.

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 of Emax 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 A1 receptor agonists.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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