Zhou Yang, Wetsel William C, Olson Steven H, Barak Lawrence S
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, United States.
Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, United States.
J Chem Inf Model. 2025 Sep 22;65(18):9713-9722. doi: 10.1021/acs.jcim.5c00972. Epub 2025 Sep 11.
The dopamine D1 receptor (D1R) is a therapeutic target for a variety of central nervous system disorders including Parkinson's disease (PD). Challenges thus arise in the development of safer D1R therapies in limiting off-target drug activity. This issue is particularly relevant to PD therapy, where L-DOPA has been the "gold standard" drug for decades despite a problematic side-effect profile. Recent studies of G-protein and β-arrestin functionally selective signaling offer new strategies for developing superior D1R orthosteric and allosteric compounds with fewer side effects. We designed a desktop-computer drug-screening platform to examine large virtual chemical libraries for allosteric compounds binding D1R intracellular loop 2 (ICL2) determinants. Two structurally distinct hits were strong enhancers of dopamine-induced β-arrestin recruitment and inhibitors of dopamine-induced G-protein activation. The lead candidate DUSBI-A3 was highly selective for D1R over closely related dopamine receptors when assessed by β-arrestin activation, providing proof-of-concept for pursuing D1R selective, biased compounds in the treatment of PD.
多巴胺D1受体（D1R）是包括帕金森病（PD）在内的多种中枢神经系统疾病的治疗靶点。因此，在开发更安全的D1R疗法以限制脱靶药物活性方面出现了挑战。这个问题与PD治疗尤为相关，尽管左旋多巴（L-DOPA）存在有问题的副作用，但它几十年来一直是“金标准”药物。最近关于G蛋白和β-抑制蛋白功能选择性信号传导的研究为开发副作用更少的优质D1R正构和变构化合物提供了新策略。我们设计了一个台式计算机药物筛选平台，以检查大型虚拟化学文库中与D1R细胞内环2（ICL2）决定簇结合的变构化合物。两种结构不同的命中化合物是多巴胺诱导的β-抑制蛋白募集的强效增强剂和多巴胺诱导的G蛋白激活的抑制剂。通过β-抑制蛋白激活评估时，先导候选物DUSBI-A3对D1R的选择性高于密切相关的多巴胺受体，为在PD治疗中寻找D1R选择性、偏向性化合物提供了概念验证。
