Unknown

Dataset Information

0

Discovery of ?-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy.


ABSTRACT: 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 (D(2)R) signaling via ?-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D(2)R agonists that display signaling bias via ?-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 ?-arrestin-biased D(2)R ligands. These compounds also represent unprecedented ?-arrestin-biased ligands for a G(i)-coupled G protein-coupled receptor (GPCR). Significantly, UNC9975, UNC0006, and UNC9994 are simultaneously antagonists of G(i)-regulated cAMP production and partial agonists for D(2)R/?-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 ?-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 ?-arrestin-biased D(2)R agonist, in wild-type mice was completely abolished in ?-arrestin-2 knockout mice. Taken together, our results suggest that ?-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, ?-arrestin-biased D(2)R ligands represent valuable chemical probes for further investigations of D(2)R signaling in health and disease.

SUBMITTER: Allen JA 

PROVIDER: S-EPMC3215024 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

altmetric image

Publications

Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy.

Allen John A JA   Yost Julianne M JM   Setola Vincent V   Chen Xin X   Sassano Maria F MF   Chen Meng M   Peterson Sean S   Yadav Prem N PN   Huang Xi-ping XP   Feng Bo B   Jensen Niels H NH   Che Xin X   Bai Xu X   Frye Stephen V SV   Wetsel William C WC   Caron Marc G MG   Javitch Jonathan A JA   Roth Bryan L BL   Jin Jian J  

Proceedings of the National Academy of Sciences of the United States of America 20111024 45


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 (D(2)R) signaling via β-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D(2)R agonists that display signaling bias via β-arrestin-ergic signaling. Through a robus  ...[more]

Similar Datasets

| S-EPMC4246677 | biostudies-literature
| S-EPMC4707817 | biostudies-literature
| S-EPMC4054005 | biostudies-literature
| S-EPMC5148701 | biostudies-literature
| S-EPMC3159699 | biostudies-literature
| S-EPMC5959776 | biostudies-literature
| S-EPMC6276031 | biostudies-literature
| S-EPMC4486767 | biostudies-literature
| S-EPMC8528033 | biostudies-literature
| S-EPMC5771956 | biostudies-literature