Discovery of β-Arrestin–Biased Dopamine D 2 Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy

逮捕 抗精神病药 G蛋白偶联受体 信号转导 药理学 多巴胺受体D2 兴奋剂 G蛋白 化学 受体 功能选择性 多巴胺 生物 细胞生物学 神经科学 医学 生物化学 精神分裂症(面向对象编程) 精神科
作者
John A. Allen,Julianne M. Yost,Vincent Setola,Xin Chen,Maria F. Sassano,Meng Chen,Sean M. Peterson,Prem N. Yadav,Xi‐Ping Huang,Bo Feng,Niels H. Jensen,Xin Che,Bo Xu,Stephen V. Frye,William C. Wetsel,Marc G. Caron,Jonathan A. Javitch,Bryan L. Roth,Jian Jin
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [Proceedings of the National Academy of Sciences]
卷期号:108 (45): 18488-18493 被引量:322
标识
DOI:10.1073/pnas.1104807108
摘要

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 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 D(2)R ligands. These compounds also represent unprecedented β-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/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 D(2)R 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 D(2)R ligands represent valuable chemical probes for further investigations of D(2)R signaling in health and disease.
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