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Background and Purpose  Target binding kinetics influence the time course of the drug effect (pharmacodynamics) both (i) directly, by affecting the time course of target occupancy, driven by the pharmacokinetics of the drug, competition with endogenous ligands and target turnover, and (ii) indirectly, by affecting signal transduction and homeostatic feedback. For dopamine D 2  receptor antagonists, it has been hypothesized that fast receptor binding kinetics cause fewer side effects, because part of the dynamics of the dopaminergic system is preserved by displacement of these antagonists.    Experimental Approach  Target binding kinetics of D 2  receptor antagonists and signal transduction after dopamine and D 2  receptor antagonist exposure were measured  in vitro . These data were integrated by mechanistic modelling, taking into account competitive binding of endogenous dopamine and the antagonist, the turnover of the second messenger cAMP and negative feedback by PDE turnover.    Key Results  The proposed signal transduction model successfully described the cellular cAMP response for 17 D 2  receptor antagonists with widely different binding kinetics. Simulation of the response to fluctuating dopamine concentrations revealed that a significant effect of the target binding kinetics on the dynamics of the signalling only occurs at endogenous dopamine concentration fluctuations with frequencies below 1 min −1 .    Conclusions and Implications  Signal transduction and feedback are important determinants of the time course of drug effects. The effect of the D 2  receptor antagonist dissociation rate constant (k off ) is limited to the maximal rate of fluctuations in dopamine signalling as determined by the dopamine k off  and the cAMP turnover.

british journal of pharmacology

In vitro  and  in silico  analysis of the effects of  D  2  receptor antagonist target binding kinetics on the cellular response to fluctuating dopamine concentrations