piperidines and bifeprunox

Bifeprunox and aripiprazole are two novel antipsychotics presenting partial agonistic activity for the D(2) and D(3) dopamine (DA) receptors. Using in vivo electrophysiological paradigms in anaesthetized rats, we have previously shown that both drugs independently inhibit the spontaneous firing and bursting activity of ventral tegmental area (VTA) dopaminergic neurons and partially reverse the suppressing effect of the full DA receptor agonist apomorphine. Moreover, we have also shown that the D(2/3) receptor antagonist haloperidol prevents the inhibitory effects of these antipsychotics, confirming their partial D(2)-like agonistic activities [L. Dahan, H. Husum, O. Mnie-Filali, J. Arnt, P. Hertel, N. Haddjeri, Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour, J. Psychopharmacol. (2009)]. In the present electrophysiological study, selective antagonists of D(2) and D(3) receptors were used to further characterize the inhibitory role of bifeprunox and aripiprazole on the D(2) and D(3) receptors in vivo. Administration of bifeprunox (250 microg/kg, i.v.) or aripiprazole (300 microg/kg, i.v.) reduced the firing activity of VTA DA neurons by 40-50%. The bursting activity was reduced by 95% and 77% by bifeprunox and aripiprazole, respectively. Systemic administration of the preferential D(3) receptor antagonist GR218,231 (200 microg/kg, i.v.) did not modify the inhibitory effect of bifeprunox or aripiprazole, either on the firing or on the bursting activity. On the other hand, the preferential D(2) receptor antagonist L741,626 (500 microg/kg, i.v.) completely blocked the inhibitory effect of both bifeprunox and aripiprazole on the VTA DA neuronal activity. The present study shows that bifeprunox and aripiprazole behave as partial D(2), but not D(3), receptor agonists in vivo, inhibiting the firing activity (preferentially the phasic activity) of VTA DA cells.

Topics: Action Potentials; Analysis of Variance; Animals; Antipsychotic Agents; Aripiprazole; Benzoxazoles; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Interactions; Indoles; Male; Neurons; Piperazines; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Sulfones; Tetrahydronaphthalenes; Ventral Tegmental Area

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 approximately 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 approximately 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.

Topics: Adenylyl Cyclases; Animals; Antipsychotic Agents; Aripiprazole; Benzamides; Benzoxazoles; Carrier Proteins; Chlorocebus aethiops; Clozapine; COS Cells; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Piperazines; Piperidines; Quinolones; Receptors, Dopamine D2; Receptors, Dopamine D3; Transfection