The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors

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

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In view of the therapeutic importance of dopamine D3 and D 2 receptors, there remains considerable interest in novel ligands. Herein, we show that the tetrahydroisoquinoline 1H-indole-2-carboxylic acid {4-[2-(cyano-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-cyclohexyl}-amide (SB269,652) behaves as an atypical, allosteric antagonist at D3 and D2 receptors. Accordingly, SB269,652 potently (low nanomolar range) abolished specific binding of [3H]nemanopride and [ 3H]spiperone to Chinese hamster ovary-transfected D3 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 Gαi3 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 Gαi3. SB269,652 (up to 10 μM) only weakly and partially (by approximately 20-30%) inhibited radioligand binding to D2 receptors. Likewise, SB269,652 only submaximally suppressed D2 receptor-mediated stimulation of Gαi3 and Gαqi5 (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 D2 receptors. Finally, Schild analysis using Gαi3 assays, and studies of radioligand association and dissociation kinetics, supported allosteric actions of SB269,652 at D 3 and D2 receptors.

Original languageEnglish
Pages (from-to)925-934
Number of pages10
JournalMolecular Pharmacology
Issue number5
StatePublished - Nov 2010


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