Premium
Partial agonist actions of aripiprazole and the candidate antipsychotics S33592, bifeprunox, N ‐desmethylclozapine and preclamol at dopamine D 2L receptors are modified by co‐transfection of D 3 receptors: potential role of heterodimer formation
Author(s) -
Novi Francesca,
Millan Mark J.,
Corsini Giovanni U.,
Maggio Roberto
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04660.x
Subject(s) - aripiprazole , quinpirole , partial agonist , agonist , receptor , chemistry , pharmacology , dopamine receptor , dopamine receptor d2 , endocrinology , medicine , biology , biochemistry , schizophrenia (object oriented programming) , psychiatry
Aripiprazole and the candidate antipsychotics, S33592, bifeprunox, N ‐desmethylclozapine (NDMC) and preclamol, are partial agonists at D 2 receptors. Herein, we examined their actions at D 2L and D 3 receptors expressed separately or together in COS‐7 cells. In D 2L receptor‐expressing cells co‐transfected with (D 3 receptor‐ insensitive ) chimeric adenylate cyclase‐V/VI, drugs reduced forskolin‐stimulated cAMP production by ∼20% versus quinpirole (48%). Further, quinpirole‐induced inhibition was blunted by aripiprazole and S33592, confirming partial agonist properties. In cells co‐transfected with equal amounts of D 2L and D 3 receptors (1 : 1), efficacies of aripiprazole and S33592 were attenuated. Further, in cells co‐transfected with D 2L and an excess of D 3 receptors (1 : 3), aripiprazole and S33592 were completely inactive , and they abolished the actions of quinpirole. Likewise, bifeprunox, NDMC and preclamol lost agonist properties in cells co‐transfected with D 2L and D 3 receptors. Accordingly, at split D 2trunk /D 3tail and D 3trunk /D 2tail chimeras, agonist actions of quinpirole were blocked by aripiprazole and S33592 that, like bifeprunox, NDMC and preclamol, were inactive alone. Conversely, when a 12 amino acid sequence in the third intracellular loop of D 3 receptors was replaced by the homologous sequence of D 2L receptors, aripiprazole, S33592, bifeprunox, NDMC and preclamol inhibited cAMP formation by ∼20% versus quinpirole (42%). Moreover, at D 2L receptor‐expressing cells co‐transfected with modified D 3i3(D2) receptors, drugs behaved as partial agonists. To summarize, low efficacy agonist actions of aripiprazole, S33592, bifeprunox, NDMC and preclamol at D 2L receptors are abrogated upon co‐expression of D 3 receptors, probably due to physical association and weakened coupling efficacy. These findings have implications for the functional profiles of antipsychotics.