title: Action of novel antipsychotics at human dopamine D3 receptors coupled to G protein and ERK1/2 activation.
abstract: The effects of new generation antipsychotic drugs (APDs) targeting dopamine D(2) and serotonin 5-HT(1A) receptors were compared with typical and atypical APDs on phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and measures of G protein activation in CHO cell lines stably expressing the human dopamine D(3) receptor. The preferential dopamine D(3) agonists (+)-7-OH-DPAT and PD128907, like dopamine and quinelorane, efficaciously stimulated ERK 1/2 phosphorylation at dopamine D(3) receptors. In contrast, in [(35)S]GTPgammaS binding experiments, (+)-7-OH-DPAT exhibited partial agonist properties, while PD128907 and quinelorane maintained full agonist properties. The preferential dopamine D(3) ligand BP 897 and the antidyskinetic sarizotan partially activated ERK 1/2 phosphorylation while exerting no agonist activity on GTPgammaS binding, suggesting signal amplification at the MAP kinase level. Antipsychotics differed in their ability to inhibit both agonist-stimulated GTPgammaS binding and ERK 1/2 phosphorylation, but all typical and atypical compounds tested acted as dopamine D(3) receptor antagonists with the exception of n-desmethylclozapine, the active metabolite of clozapine, which partially activated dopamine D(3) receptor-mediated ERK 1/2 phosphorylation. Among the new generation dopamine D(2)/serotonin 5-HT(1A) antipsychotics, only F 15063 and SLV313 acted as pure dopamine D(3) receptor antagonists, bifeprunox was highly efficacious whereas SSR181507 and aripiprazole showed marked partial agonist properties for ERK 1/2 phosphorylation. In contrast, in the GTPgammaS binding study, aripiprazole was devoid of agonist properties and bifeprunox, and to an even lesser extent SSR181507, only weakly stimulated GTPgammaS binding. In summary, these findings underline the differences of dopamine D(3) properties of new generation antipsychotics which may need to be considered in understanding their diverse therapeutic actions.
authors.affiliation: Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, F 81106 Castres Cedex, France. liesbeth.bruins.slot@pierre-fabre.com
authors.forename: Liesbeth A
authors.initials: LA
authors.lastname: Bruins Slot
authors.forename: Christiane
authors.initials: C
authors.lastname: Palmier
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Tardif
authors.forename: Didier
authors.initials: D
authors.lastname: Cussac
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D050637:Receptors, Dopamine D3 / Q000502:physiology*; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D050637:Receptors, Dopamine D3; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D048049:Extracellular Signal-Regulated MAP Kinases; D019204:GTP-Binding Proteins