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
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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