The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D2 receptor (D2R) targeted molecules that may be therapeutically advantageous for the treatment of certain neuropsychiatric or basal ganglia related disorders. Here we describe the synthesis of a novel series of D2R agonists linking the D2R unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved D2R affinity and selectivity over sumanirole. Extensive in vitro functional studies and bias factor analysis led to the identification of a novel class of highly potent Go-protein biased full D2R agonists with more than 10-fold and 1000-fold bias selectivity toward activation of specific G-protein subtypes and β-arrestin, respectively. Intracellular electrophysiological recordings from midbrain dopamine neurons demonstrated that Go-protein selective agonists can elicit prolonged ligand-induced GIRK activity via D2Rs, which may be beneficial in the treatment of dyskinesias associated with dopamine system dysfunction.

中文翻译：

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新颖而有效的多巴胺D2受体高蛋白偏倚激动剂。

针对G蛋白偶联受体（GPCR）的功能偏向和对生理有益的配体的发现为设计多巴胺D2受体（D2R）靶向分子提供了动力，这些分子可能在治疗某些神经精神病或基底神经节相关疾病方面具有治疗优势。在这里，我们描述了一系列新的D2R激动剂的合成，这些D2R激动剂将D2R无偏激动剂sumanirole与优先的次级分子片段连接在一起。所得的配体显示出优于舒马尼罗的D2R亲和力和选择性。广泛的体外功能研究和偏倚因素分析导致鉴定出一类新型的强效Go蛋白偏向全D2R激动剂，对特定G蛋白亚型和β-激活的偏向选择性超过10倍和1000倍。抑制蛋白 分别。中脑多巴胺神经元的细胞内电生理记录表明，Go蛋白选择性激动剂可通过D2Rs延长配体诱导的GIRK活性，这可能对治疗与多巴胺系统功能障碍有关的运动障碍有益。