In vitro and in silico analysis of the effects of D2 receptor antagonist target binding kinetics on the cellular response to fluctuating dopamine concentrations

Author(s):
Wite, W.E.A. de; Versfelt, J.W.; Kuzikov, M.; Rolland, S.; Georgi, V.; Gribbon, P.; Gul, S.; Huntjens, D.; Graaf, P.H. van der; Danhof, M. (0000-0002-2319-6830); Fernández-Montalván, A.; Witt, G.; Lange, E.C.M. de (0000-0001-8303-1117)
Published
2018
Publication type
Article / Letter to editor

Abstract

and the cAMP turnover.

.

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.

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. CONCLUSIONS AND IMPLICATIONS KEY RESULTS BACKGROUND AND PURPOSE EXPERIMENTAL APPROACH

Date issued
2018-12-01
Language
English
Is part of
British Journal of Pharmacology (2018), Vol. 175, no. 21, p. 4121-4136
hdl
1887/69425
doi
10.1111/bph.14456