RT Journal Article SR Electronic T1 Dynamic Dopamine-Antagonist Interactions at Recombinant Human Dopamine D2short Receptor: Dopamine-Bound versus Antagonist-Bound Receptor States JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 133 OP 140 VO 297 IS 1 A1 Petrus J. Pauwels A1 Fréderic Finana A1 Stéphanie Tardif A1 Thierry Wurch A1 Francis C. Colpaert YR 2001 UL http://jpet.aspetjournals.org/content/297/1/133.abstract AB Antipsychotic drugs comprise a wide range of structurally diverse compounds and are considered to be antagonists at dopamine D2 receptors. High-resolution kinetic analyses of their antagonist properties was performed by monitoring dynamic dopamine (DA)-antagonist interactions at the recombinant human dopamine D2short receptor. Time-dependent Ca2+ responses were measured following activation of a chimeric Gαq/o protein in Chinese hamster ovary-K1 cells. DA (10 μM) induced a rapid, high-magnitude Ca2+ response (Tmax = 13.2 ± 0.7 s) followed by a low-magnitude phase, which continued throughout 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 other antagonists 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 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 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 D2shortreceptor. The American Society for Pharmacology and Experimental Therapeutics