Aripiprazole and the candidate antipsychotics, S33592, bifeprunox, N-desmethylclozapine (NDMC) and preclamol, are partial agonists at D2 receptors. Herein, we examined their actions at D2L and D3 receptors expressed separately or together in COS-7 cells. In D2L receptor-expressing cells cotransfected with (D3 receptor-insensitive) chimeric adenylate cyclase-V/VI, drugs reduced forskolin-stimulated cAMP production by 20% versus quinpirole (48%). Further, quinpiroleinduced inhibition was blunted by aripiprazole and S33592, confirming partial agonist properties. In cells co-transfected with equal amounts of D2L and D3 receptors (1 : 1), efficacies of aripiprazole and S33592 were attenuated. Further, in cells co-transfected with D2L and an excess of D3 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 cotransfected with D2L and D3 receptors. Accordingly, at split D2trunk/D3tail and D3trunk/D2tail 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 D3 receptors was replaced by the homologous sequence of D2L receptors, aripiprazole, S33592, bifeprunox, NDMC and preclamol inhibited cAMP formation by 20% versus quinpirole (42%). Moreover, at D2L receptor-expressing cells co-transfected with modified D3i3(D2) receptors, drugs behaved as partial agonists. To summarize, low efficacy agonist actions of aripiprazole, S33592, bifeprunox, NDMC and preclamol at D2L receptors are abrogated upon coexpression of D3 receptors, probably due to physical association and weakened coupling efficacy. These findings have implications for the functional profiles of antipsychotics.

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

MAGGIO, Roberto
2007

Abstract

Aripiprazole and the candidate antipsychotics, S33592, bifeprunox, N-desmethylclozapine (NDMC) and preclamol, are partial agonists at D2 receptors. Herein, we examined their actions at D2L and D3 receptors expressed separately or together in COS-7 cells. In D2L receptor-expressing cells cotransfected with (D3 receptor-insensitive) chimeric adenylate cyclase-V/VI, drugs reduced forskolin-stimulated cAMP production by 20% versus quinpirole (48%). Further, quinpiroleinduced inhibition was blunted by aripiprazole and S33592, confirming partial agonist properties. In cells co-transfected with equal amounts of D2L and D3 receptors (1 : 1), efficacies of aripiprazole and S33592 were attenuated. Further, in cells co-transfected with D2L and an excess of D3 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 cotransfected with D2L and D3 receptors. Accordingly, at split D2trunk/D3tail and D3trunk/D2tail 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 D3 receptors was replaced by the homologous sequence of D2L receptors, aripiprazole, S33592, bifeprunox, NDMC and preclamol inhibited cAMP formation by 20% versus quinpirole (42%). Moreover, at D2L receptor-expressing cells co-transfected with modified D3i3(D2) receptors, drugs behaved as partial agonists. To summarize, low efficacy agonist actions of aripiprazole, S33592, bifeprunox, NDMC and preclamol at D2L receptors are abrogated upon coexpression of D3 receptors, probably due to physical association and weakened coupling efficacy. These findings have implications for the functional profiles of antipsychotics.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11697/11853
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 40
  • ???jsp.display-item.citation.isi??? 36
social impact