Abstract
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.
Footnotes
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Send reprint requests to: Dr. Peter J. Pauwels, Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, 81106 Castres Cédex, France. E-mail:peter.pauwels{at}pierre-fabre.com
- Abbreviations:
- DA
- dopamine
- CHO
- Chinese hamster ovary
- PCR
- polymerase chain reaction
- (+)-NPA
- S-(+)-propylnorapomorphine
- (+)-UH 232
- cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin
- S 14066
- 3-(1-(benzocyclobutan-1-ylmethyl)piperidin-4-yl)-6-fluoro-1,2-benzisoxazole
- Received September 22, 2000.
- Accepted December 5, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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