8-Amido-chromen-4-one-2-carboxylic acid derivatives were identified as novel agonists at the G protein-coupled orphan receptor GPR35. They were characterized by a β-arrestin recruitment assay and optimized to obtain agonists with nanomolar potency for the human GPR35. The compounds were found to exhibit high selectivity versus the related GPR55. The most potent agonists were 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (85, EC₅₀ 12.1 nM) and 6-bromo-8-(2-chloro-4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (90, EC₅₀ 11.1 nM), both of which were >1700-fold selective versus GPR55. Most compounds were considerably less potent at rat and mouse than at human GPR35. 6-Bromo-8-(2-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (87) was the only derivative that activated GPR35 of all three species at similar, low micromolar concentration. Compounds 85 and 90 are the most potent agonists at the human GPR35 known to date and might thus serve as powerful pharmacological tools to further elucidate the receptor’s (patho)physiological role and its potential as a future drug target.

中文翻译：

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8-Benzamidochromen-4-one-2-羧酸：孤儿G蛋白偶联受体GPR35的强效和选择性激动剂。

在G蛋白偶联的孤儿受体GPR35上，鉴定了8-酰胺基色烯-4-一-2-羧酸衍生物是新型激动剂。通过β-arrestin募集试验对它们进行了表征，并对其进行了优化，以获得对人GPR35具有纳摩尔效价的激动剂。发现该化合物与相关的GPR55相比具有高选择性。最有效的激动剂是6-溴8-（4-甲氧基苯甲酰胺基）-4-氧代-4 H-亚甲基-2-羧酸（85，EC ₅₀ 12.1 nM）和6-溴8-（2-氯- 4-甲氧基苯甲酰胺基）-4-氧代-4 H-亚甲基-2-羧酸（90，EC ₅₀11.1 nM），二者相对于GPR55的选择性都> 1700倍。与人类GPR35相比，大多数化合物在大鼠和小鼠上的效力明显较低。6-溴-8-（2-甲氧基苯甲酰胺基）-4-氧代-4 H-亚甲基-2-羧酸（87）是在相似的低微摩尔浓度下激活所有三个物种的GPR35的唯一衍生物。化合物85和90是迄今为止已知的人类GPR35上最有效的激动剂，因此可作为有力的药理学工具，进一步阐明受体的（病理）生理作用及其作为未来药物靶标的潜力。