Discovery of β-Arrestin–Biased Dopamine D2 Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy
Proceedings of the National Academy of Sciences, 2011•National Acad Sciences
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 D2 receptor (D2R) signaling via β-
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 β-
arrestin–ergic signaling. Through a robust diversity-oriented modification of the scaffold …
and side-effect profiles is essential for developing safer and more effective therapies. Recent
work has highlighted noncanonical modes of dopamine D2 receptor (D2R) signaling via β-
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 β-
arrestin–ergic signaling. Through a robust diversity-oriented modification of the scaffold …
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 D2 receptor (D2R) signaling via β-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 β-arrestin–ergic 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 β-arrestin–biased D2R ligands. These compounds also represent unprecedented β-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/β-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 β-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 β-arrestin–biased D2R agonist, in wild-type mice was completely abolished in β-arrestin-2 knockout mice. Taken together, our results suggest that β-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, β-arrestin–biased D2R ligands represent valuable chemical probes for further investigations of D2R signaling in health and disease.
National Acad Sciences