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.
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.
Novi
Francesca
F
Department of Neuroscience, University of Pisa, Pisa, Italy.
Millan
Mark J
MJ
Corsini
Giovanni U
GU
Maggio
Roberto
R
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001549:Benzamides / Q000493:pharmacokinetics; D001583:Benzoxazoles / Q000494:pharmacology; D019556:COS Cells; D002352:Carrier Proteins / Q000187:drug effects; D002522:Chlorocebus aethiops; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D050637:Receptors, Dopamine D3 / Q000502:physiology*; D014162:Transfection / Q000379:methods
D014150:Antipsychotic Agents; D001549:Benzamides; D001583:Benzoxazoles; D002352:Carrier Proteins; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010879:Piperazines; D010880:Piperidines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C058272:norclozapine; D000068180:Aripiprazole; C026539:preclamol; C509981:bifeprunox; D000262:Adenylyl Cyclases; D003024:Clozapine; C030265:nemonapride