Action of novel antipsychotics at human dopamine D3 receptors coupled to G protein and ERK1/2 activation

The effects of new generation antipsychotic drugs (APDs) targeting dopamine D2 and serotonin 5-HT1A 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 D3 receptor. The preferential dopamine D3 agonists (+)-7-OH-DPAT and PD128907, like dopamine and quinelorane, efficaciously stimulated ERK 1/2 phosphorylation at dopamine D3 receptors. In contrast, in [35S]GTPγS binding experiments, (+)-7-OH-DPAT exhibited partial agonist properties, while PD128907 and quinelorane maintained full agonist properties. The preferential dopamine D3 ligand BP 897 and the antidyskinetic sarizotan partially activated ERK 1/2 phosphorylation while exerting no agonist activity on GTPγS binding, suggesting signal amplification at the MAP kinase level. Antipsychotics differed in their ability to inhibit both agonist-stimulated GTPγS binding and ERK 1/2 phosphorylation, but all typical and atypical compounds tested acted as dopamine D3 receptor antagonists with the exception of n-desmethylclozapine, the active metabolite of clozapine, which partially activated dopamine D3 receptor-mediated ERK 1/2 phosphorylation. Among the new generation dopamine D2/serotonin 5-HT1A antipsychotics, only F 15063 and SLV313 acted as pure dopamine D3 receptor antagonists, bifeprunox was highly efficacious whereas SSR181507 and aripiprazole showed marked partial agonist properties for ERK 1/2 phosphorylation. In contrast, in the GTPγS binding study, aripiprazole was devoid of agonist properties and bifeprunox, and to an even lesser extent SSR181507, only weakly stimulated GTPγS binding. In summary, these findings underline the differences of dopamine D3 properties of new generation antipsychotics which may need to be considered in understanding their diverse therapeutic actions.