G protein-biased mu-opioid receptor (MOR) agonists have been developed as promising new potent analgesic drugs with fewer adverse side effects than standard MOR agonists. PZM21 represents a unique chemotype unrelated to known opioids, which makes it a desirable lead for modification to find analgesics with new chemical entities. In the present study, we synthesized and tested novel PZM21 derivatives as potent biased MOR agonists by introducing a benzodioxolane group to replace the hydroxybenzene of PZM21. The new compounds displayed more potent analgesic activities in vivo and greater bias toward G protein signaling in vitro than did PZM21. These results suggest that the benzodioxolane group is essential for the maintenance of bias. Compounds 7 i ((S)-1-(3-(benzo[d][1,3]dioxol-4-yl)-2-(dimethylamino)propyl)-3-phenethylurea) and 7 j ((S)-1-(3-(benzo[d][1,3]dioxol-4-yl)-2-(dimethylamino)propyl)-3-benzylurea) could serve as new leads for further modifications to find novel biased MOR agonists with greater G protein signaling potency and less β-arrestin-2 recruitment.

中文翻译：

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有偏见的阿片类阿片受体激动剂治疗疼痛的发现。

G蛋白偏向型阿片受体（MOR）激动剂已被开发为有前景的新型有效止痛药，与标准MOR激动剂相比，副作用更少。PZM21代表与已知阿片类药物无关的独特化学型，这使其成为进行修饰以寻找具有新化学实体的止痛药的理想先导。在本研究中，我们通过引入苯并二氧戊环基团取代PZM21的羟基苯，合成并测试了新型PZM21衍生物作为强效的MOR激动剂。与PZM21相比，新化合物在体内显示出更强的镇痛活性，并在体外对G蛋白信号传导产生更大的偏见。这些结果表明，苯并二氧戊环基团对于维持偏倚是必不可少的。化合物7 i（（S）-1-（3-（苯并[d] [1，