Distinct functional profiles of partial agonist antipsychotics in cAMP and β-arrestin signaling mechanisms of dopamine D2 and D3 receptors in vitro.

Aripiprazole, brexpiprazole and cariprazine represent a new generation of atypical antipsychotics with partial agonist activity at dopamine D2 and D3 receptors. So far, the functional activity of these partial agonists has mainly been studied at G-protein-dependent cyclic adenosine monophosphate (cAMP) signaling pathways of D2 and D3 receptors. While their effects at D2 receptor-mediated β-arrestin translocation were relatively well characterized the comparative investigation at D3-dependent β-arrestin translocation is still largely missing. Moreover, antagonism of these partial agonists either at D2 or D3 receptors has not been studied at multiple cellular signaling pathways. In this study, we compared the agonist and antagonist features of aripiprazole, brexpiprazole, cariprazine on dopamine receptor-mediated cAMP and β-arrestin pathways in multiple cell lines expressing recombinant human D2 or D3 receptors using homogeneous time-resolved fluorescence and luminescent enzyme fragment complementation technologies. We demonstrated that the three partial agonists display qualitatively similar functional profile at D2 receptor-mediated cAMP and β-arrestin pathways. While cariprazine showed partial agonism and partial antagonism at D3 receptor-mediated β-arrestin translocation, aripiprazole and brexpiprazole displayed only weak or no agonist but potent antagonist activity. These data suggest differentiated mechanism of action of cariprazine at the D3 receptor signaling compared to aripiprazole and brexpiprazole.