Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18488-93. doi: 10.1073/pnas.1104807108. Epub 2011 Oct 24.
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.
阐明抗精神病药疗效和副作用特征所必需的关键信号转导途径对于开发更安全、更有效的治疗方法至关重要。最近的工作强调了通过β-arrestin 发挥多巴胺 D2 受体 (D2R) 信号的非典型模式对于抗精神病药和抗躁狂药的治疗作用很重要。因此，我们试图创建通过β-arrestin 信号显示信号偏向的独特 D2R 激动剂。通过对阿立哌唑 (1) 代表的支架进行强大的多样性导向修饰，我们发现 UNC9975 (2)、UNC0006 (3) 和 UNC9994 (4) 是前所未有的β-arrestin 偏向性 D2R 配体。这些化合物也是前所未有的 G(i) 偶联 G 蛋白偶联受体 (GPCR) 的β-arrestin 偏向性配体。重要的是，UNC9975 同时是 G(i) 调节的 cAMP 产生的拮抗剂和 D2R/β-arrestin-2 相互作用的部分激动剂。重要的是，UNC9975 在体内未引起运动副作用的情况下，在近交 C57BL/6 小鼠中表现出有效的抗精神病样活性。β-arrestin-2 的基因缺失同时减弱了 UNC9975 的抗精神病作用，并将其转化为一种具有高诱导僵住倾向的典型抗精神病药物。同样，UNC9994 作为一种极其偏向β-arrestin 的 D2R 激动剂，在野生型小鼠中显示出的抗精神病样活性在β-arrestin-2 敲除小鼠中完全消失。总之，我们的结果表明，β-arrestin 信号和募集可以同时对抗精神病药的疗效做出重大贡献，并防止运动副作用。这些功能选择性的、β-arrestin 偏向性的 D2R 配体代表了用于进一步研究 D2R 信号在健康和疾病中的有价值的化学探针。
