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The Tetrahydroisoquinoline Derivative SB269,652 Is an Allosteric Antagonist at Dopamine D 3 and D 2 Receptors

2010; American Society for Pharmacology and Experimental Therapeutics; Volume: 78; Issue: 5 Linguagem: Inglês

10.1124/mol.110.065755

1521-0111

Elena Silvano, Mark J. Millan, Clotilde Mannoury la Cour, Yang Han, Lihua Duan, Suzy A. Griffin, Robert R. Luedtke, Gabriella Aloisi, Mario Rossi, Francesca Zazzeroni, Jonathan A. Javitch, Roberto Maggio,

Neurotransmitter Receptor Influence on Behavior

In view of the therapeutic importance of dopamine D 3 and D 2 receptors, there remains considerable interest in novel ligands. Herein, we show that the tetrahydroisoquinoline 1 H -indole-2-carboxylic acid {4-[2-(cyano-3,4-dihydro-1 H -isoquinolin-2-yl)-ethyl]-cyclohexyl}-amide (SB269,652) behaves as an atypical, allosteric antagonist at D 3 and D 2 receptors. Accordingly, SB269,652 potently (low nanomolar range) abolished specific binding of [ 3 H]nemanopride and [ 3 H]spiperone to Chinese hamster ovary-transfected D 3 receptors when radioligands were used at 0.2 and 0.5 nM, respectively. However, even at high concentrations (5 μM), SB269,652 only submaximally inhibited the specific binding of these radioligands when they were employed at 10-fold higher concentrations. By analogy, although SB269,652 potently blocked D 3 receptor-mediated activation of Gα i3 and phosphorylation of extracellular-signal-regulated kinase (ERK)1/2, when concentrations of dopamine were increased by 10-fold, from 1 μM to 10 μM, SB269,652 only submaximally inhibited dopamine-induced stimulation of Gα i3 . SB269,652 (up to 10 μM) only weakly and partially (by approximately 20–30%) inhibited radioligand binding to D 2 receptors. Likewise, SB269,652 only submaximally suppressed D 2 receptor-mediated stimulation of Gα i3 and Gα qi5 (detected with the aequorin assay) and phosphorylation of ERK1/2 and Akt. Furthermore, SB269,652 only partially (35%) inhibited the dopamine-induced recruitment of β-arrestin2 to D 2 receptors. Finally, Schild analysis using Gα i3 assays, and studies of radioligand association and dissociation kinetics, supported allosteric actions of SB269,652 at D 3 and D 2 receptors.