GPR27 belongs, with GPR85 and GPR173, to a small subfamily of three receptors called “Super-Conserved Receptors Expressed in the Brain” (SREB). It has been postulated to participate in key physiological processes such as neuronal plasticity, energy metabolism, and pancreatic β-cell insulin secretion and regulation. Recently, we reported the first selective GPR27 agonist, 2,4-dichloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (I, pEC₅₀ 6.34, E_max 100%). Here, we describe the synthesis and structure-activity relationships of a series of new derivatives and analogs of I. All products were evaluated for their ability to activate GPR27 in an arrestin recruitment assay. As a result, agonists were identified with a broad range of efficacies including partial and full agonists, showing higher efficacies than the lead compound I. The most potent agonist was 4-chloro-2,5-difluoro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7y, pEC₅₀ 6.85, E_max 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC₅₀ 6.04, E_max 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC₅₀ 5.99, E_max 123%). Docking studies predicted the putative binding site and interactions of agonist 7p with GPR27. Selected potent agonists were found to be soluble and devoid of cellular toxicity within the range of their pharmacological activity. Therefore, they represent important new tools to further characterize the (patho)physiological roles of GPR27.

GPR27 与 GPR85 和 GPR173 一起属于三个受体的小亚家族，称为“大脑中表达的超保守受体”（SREB）。它被假定参与关键的生理过程，如神经元可塑性、能量代谢和胰腺 β 细胞胰岛素分泌和调节。最近，我们报道了第一个选择性 GPR27 激动剂，2,4-二氯-N- (4-( N-苯基氨磺酰基)苯基)苯甲酰胺 ( I , pEC ₅₀ 6.34, E _max 100%)。在这里，我们描述了I的一系列新衍生物和类似物的合成和构效关系。. 在抑制蛋白募集测定中评估了所有产品激活 GPR27 的能力。结果，确定了具有广泛功效的激动剂，包括部分激动剂和完全激动剂，显示出比先导化合物I更高的功效。最有效的激动剂是 4-chloro-2,5-difluoro- N- (4-( N - phenylsulfamoyl)phenyl)benzamide ( 7y , pEC ₅₀ 6.85, E _max 37%)，功效更高的激动剂是 4-氯-2-甲基-N- (4-( N-苯基氨磺酰基)苯基)苯甲酰胺（7p，pEC ₅₀ 6.04，E _max 123%）和 2-溴-4-氯-N-(4-( N-苯基氨磺酰基)苯基)苯甲酰胺( 7r , pEC ₅₀ 5.99, E _max 123%)。对接研究预测了激动剂7p与 GPR27 的推定结合位点和相互作用。发现选定的强效激动剂在其药理活性范围内是可溶的并且没有细胞毒性。因此，它们代表了进一步表征 GPR27 的（病理）生理作用的重要新工具。