In this work, we explored the molecular framework of the known CB1R allosteric modulator PSNCBAM-1 with the aim to generate new bioactive analogs and to deepen the structure-activity relationships of this type of compounds. In particular, the introduction of a NH group between the pyridine ring and the phenyl nucleus generated the amino-phenyl-urea derivative SN15b that behaved as a positive allosteric modulator (PAM), increasing the CB1R binding affinity of the orthosteric ligand CP55,940. The functional activity was evaluated using serum response element (SRE) assay, which assesses the CB1R-dependent activation of the MAPK/ERK signaling pathway. SN15b and the biphenyl-urea analog SC4a significantly inhibited the response produced by CP55,940 in the low µM range, thus behaving as negative allosteric modulators (NAMs). The new derivatives presented here provide further insights about the modulation of CB1R binding and functional activity by allosteric ligands.

在这项工作中，我们探索了已知的CB1R变构调节剂PSNCBAM-1的分子框架，目的是生成新的生物活性类似物并加深此类化合物的构效关系。特别地，在吡啶环和苯基核之间引入NH基团产生了氨基-苯基-脲衍生物SN15b，其充当正变构调节剂（PAM），从而增加了正构配体CP55,940的CB1R结合亲和力。使用血清反应元件（SRE）分析评估功能活性，该分析评估MAPK / ERK信号通路的CB1R依赖性激活。SN15b和联苯脲类似物SC4a在低µM范围内显着抑制了CP55,940产生的响应，因此表现为负变构调节剂（NAM）。本文介绍的新衍生物提供了有关变构配体对CB1R结合的调节和功能活性的进一步见解。