Premium
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
Author(s) -
Witte Wilhelmus E A,
Versfelt Joost W,
Kuzikov Maria,
Rolland Solene,
Georgi Victoria,
Gribbon Philip,
Gul Sheraz,
Huntjens Dymphy,
Graaf Piet Hein,
Danhof Meindert,
FernándezMontalván Amaury,
Witt Gesa,
Lange Elizabeth C M
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14456
Subject(s) - dopamine , dopamine receptor , dopamine receptor d2 , receptor , dopaminergic , biophysics , signal transduction , chemistry , receptor–ligand kinetics , antagonist , biology , pharmacology , medicine , endocrinology , biochemistry
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.