Dynamic Dopamine-Antagonist Interactions at Recombinant Human Dopamine D_2short Receptor: Dopamine-Bound versus Antagonist-Bound Receptor States

摘要

Antipsychotic drugs comprise a wide range of structurally di- verse compounds and are considered to be antagonists at dopamine O2 receptors. High-resolution kinetic analyses of their antagonist properties was performed by monitoring dy- namic dopamine (OA)-antagonist interactions at the recombi- nant human dopamine O2short receptor. Time-dependent Ca2+ responses were measured following activation of a chimeric G"q/Q protein in Chinese hamster ovary-K1 cells. OA (10 ILM) induced a rapid, high-magnitude Ca2+ response (T max = 13.2+- 0.7 s) followed bya low-magnitude phase, which con- tinued throughout the recorded time period (15 min). Of a large[ series of putative OA antagonists, ( + )-UH 232 and bromer- guride demonstrated positive, OA-Iike intrinsic activity at the I presumably unoccupied, OA-free receptor; the other antago-nists being silent. Antagonists differed in terms of their abilities to prevent the high-magnitude Ca2+ phase in the antagonist- bound receptor state, and to reverse the low-magnitude Ca2+ phase in the DA-bound state. The benzamide derivatives tro- papride and nemonapride fully antagonized both the high- and low-magnitude Ca2+ response. Haloperidol, risperidone, and S 14066 also antagonized both responses but with a maximal effect of only 62 to 79%. Although preventing the high-magni- tude response {85-95%), the further putative antagonists {+)- butaclamol {6%), bromerguride {27%), and domperidone {41 %) reversed the low-magnitude response only weakly and partially. These Ca2+ data indicate that putative DA antagonists act differently, in particular, at the DA-bound D2short receptor.