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

Abstract

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.