Dynamic dopamine-antagonist interactions at recombinant human dopamine D-2short receptor: Dopamine-bound versus antagonist-bound receptor states

Antipsychotic drugs comprise a wide range of structurally diverse compounds and are considered to be antagonists at dopamine D-2 receptors. High-resol ution kinetic analyses of their antagonist properties was performed by moni toring dynamic dopamine (DA)-antagonist interactions at the recombinant hum an dopamine D-2short receptor. Time-dependent Ca2+ responses were measured following activation of a chimeric G(alphaq/o) protein in Chinese hamster o vary-K1 cells. DA (10 muM) induced a rapid, high-magnitude Ca2+ response (T -max = 13.2 +/- 0.7 s) followed by a low-magnitude phase, which continued t hroughout the recorded time period (15 min). Of a large series of putative DA antagonists, (+)-UH 232 and bromerguride demonstrated positive, DA-like intrinsic activity at the presumably unoccupied, DA-free receptor; the othe r antagonists being silent. Antagonists differed in terms of their abilitie s 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 tropapride 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- magnitude response (85-95%), the fur ther putative antagonists (+)-butaclamol (6%), bromerguride (27%), and domp eridone (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 D-2short receptor.