S-33592

The effects of aripiprazole, S33592, bifeprunox, N-desmethylclozapine and preclamol acting as partial agonists on recombinant D(2L) and D(3) receptors expressed both separately and concomitantly in COS-7 cells are evaluated here. Aripiprazole, S33592, bifeprunox, N-desmethylclozapine and preclamol behave as partial agonists on D(2L) receptors coupled with adenylyl cyclase, but they behave as antagonists on co-expression of D(3) with D(2L) receptors. These data raise the intriguing hypothesis that antipsychotic actions of "partial agonists" such as aripiprazole may not reflect inefficient stimulation of D(2) and/or D(3) receptors but, by analogy with other antipsychotics, may instead represent a blockade of D(2)/D(3) heterodimers (and/or D(3) receptors) that are "weakly" coupled to transduction mechanisms postsynaptically of the dopaminergic pathway.

Aripiprazole and the candidate antipsychotics, S33592, bifeprunox,N‐desmethylclozapine (NDMC) and preclamol, are partial agonists at D2receptors. Herein, we examined their actions at D2Land D3receptors expressed separately or together in COS‐7 cells. In D2Lreceptor‐expressing cells co‐transfected with (D3receptor‐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 D2LandD3receptors (1 : 1), efficacies of aripiprazole and S33592 were attenuated. Further, in cells co‐transfected with D2Land anexcessof D3receptors (1 : 3), aripiprazole and S33592 were completelyinactive, and theyabolishedthe actions of quinpirole. Likewise, bifeprunox, NDMC and preclamol lost agonist properties in cells co‐transfected with D2LandD3receptors. Accordingly, at split D2trunk/D3tailand D3trunk/D2tailchimeras, agonist actions of quinpirole were blocked by aripiprazole and S33592 that, like bifeprunox, NDMC and preclamol, wereinactivealone. Conversely, when a 12 amino acid sequence in the third intracellular loop of D3receptors was replaced by the homologous sequence of D2Lreceptors, aripiprazole, S33592, bifeprunox, NDMC and preclamol inhibited cAMP formation by ∼20% versus quinpirole (42%). Moreover, at D2Lreceptor‐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 D2Lreceptors are abrogated upon co‐expression of D3receptors, probably due to physical association and weakened coupling efficacy. These findings have implications for the functional profiles of antipsychotics.