Discovery of β-Arrestin-Biased Dopamine D2 Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy

Elucidating the key signal transduction pathways essential for both antipsychotic efficacy and side-effect profiles is essential for developing safer and more effective therapies. Recent work has highlighted noncanonical modes of dopamine D-2 receptor (D2R) signaling via beta-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D2R agonists that display signaling bias via beta-arrestinergic signaling. Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented beta-arrestin-biased D2R ligands. These compounds also represent unprecedented beta-arrestin-biased ligands for a Gi-coupled G protein-coupled receptor (GPCR). Significantly, UNC9975, UNC0006, and UNC9994 are simultaneously antagonists of Gi-regulated cAMP production and partial agonists for D2R/beta-arrestin-2 interactions. Importantly, UNC9975 displayed potent antipsychotic-like activity without inducing motoric side effects in inbred C57BL/6 mice in vivo. Genetic deletion of beta-arrestin-2 simultaneously attenuated the antipsychotic actions of UNC9975 and transformed it into a typical antipsychotic drug with a high propensity to induce catalepsy. Similarly, the antipsychotic-like activity displayed by UNC9994, an extremely beta-arrestin-biased D2R agonist, in wild-type mice was completely abolished in beta-arrestin-2 knockout mice. Taken together, our results suggest that beta-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, beta-arrestin-biased D2R ligands represent valuable chemical probes for further investigations of D2R signaling in health and disease.